Naglazyme

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



2 

▼This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Naglazyme 1 mg/ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of solution contains 1 mg galsulfase. One vial of 5 ml contains 5 mg galsulfase. 
 
Galsulfase is a recombinant form of human N-acetylgalactosamine 4-sulfatase and is produced by 
recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture. 
 
Excipients 
 
Each 5 ml vial contains 0.8 mmol (18.4 mg) of sodium. 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
A clear to slightly opalescent, and colourless to pale yellow solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Naglazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed 
diagnosis of Mucopolysaccharidosis VI (MPS VI; N-acetylgalactosamine 4-sulfatase deficiency; 
Maroteaux-Lamy syndrome) (see section 5.1). 
 
A key issue is to treat children aged <5 years suffering from a severe form of the disease, even though 
children <5 years were not included in the pivotal phase 3 study. Limited data are available in patients 
< 1 year of age (see section 5.1). 
 
4.2 Posology and method of administration 
 
As for all lysosomal genetic disorders, it is of primary importance, especially in severe forms, to 
initiate treatment as early as possible, before appearance of non-reversible clinical manifestations of 
the disease. 
 
Naglazyme treatment should be supervised by a physician experienced in the management of patients 
with MPS VI or other inherited metabolic diseases. Administration of Naglazyme should be carried 
out in an appropriate clinical setting where resuscitation equipment to manage medical emergencies 
would be readily available. 
 
Posology 
 
The recommended dose regimen for galsulfase is 1 mg/kg body weight administered once every week 
as an intravenous infusion over 4 hours.  



3 

 
Special populations 
 
Elderly 
The safety and efficacy of Naglazyme in patients older than 65 years has not been established, and no 
alternative dose regimen can be recommended in these patients. 
 
Renal and hepatic impairment 
The safety and efficacy of Naglazyme in patients with renal or hepatic insufficiency have not been 
evaluated (see section 5.2) and no alternative dose regimen can be recommended in these patients. 
 
Paediatric population 
There is no evidence for special considerations when Naglazyme is administered to the paediatric 
population. Currently available data are described in section 5.1. 
 
Method of administration 
 
The initial infusion rate is adjusted so that approximately 2.5% of the total solution is infused during 
the first hour, with infusion of the remaining volume (approximately 97.5%) over the next 3 hours.  
 
100 ml infusion bags should be considered for patients who are susceptible to fluid volume overload 
and weigh less than 20 kg; in this case the infusion rate (ml/min) should be decreased so that the total 
duration remains no less than 4 hours.  
 
For information on pre-treatment see section 4.4 and for further instructions see section 6.6. 
 
4.3 Contraindications 
 
Severe or life-threatening hypersensitivity to the active substance or to any of the excipients, if 
hypersensitivity is not controllable. 
 
4.4 Special warnings and precautions for use 
 
Management of compromised airways 
 
Caution must be exercised in the management and treatment of patients with compromised airways by 
limitation or careful monitoring of antihistamine and other sedative medicinal product use. Institution 
of positive–airway pressure during sleep as well as potential tracheostomy in clinically appropriate 
situations should also be considered. 
 
Patients who present with an acute febrile or respiratory illness may need to have their Naglazyme 
infusions delayed. 
 
Management of infusion-associated reactions 
 
Patients treated with Naglazyme have developed infusion-associated reactions (IARs), defined as any 
adverse reactions occurring during the infusion or until the end of the infusion day (see section 4.8). 
 
Based on data obtained during Naglazyme clinical trials, the majority of patients are expected to 
develop IgG antibodies to galsulfase within 4-8 weeks of treatment initiation.  
 
In the Naglazyme clinical trials, IARs were usually manageable by interrupting or slowing the rate of 
infusion and by (pre-) treating the patient with antihistamines and/or antipyretics (paracetamol), thus 
enabling the patient to continue treatment. 
 
As there is little experience on resumption of treatment following prolonged interruption, caution is to 
be used due to the theoretical increased risk of hypersensitivity reaction. 



4 

 
With administration of Naglazyme it is recommended that patients be administered pre-treatment 
medicinal products (antihistamines with or without antipyretics) approximately 30-60 minutes prior to 
the start of the infusion, to minimise the potential occurrence of IARs. 
 
In case of a mild or moderate IAR, treatment with antihistamines and paracetamol should be 
considered and/or a reduction in the infusion rate to half the rate at which the reaction occurred. 
 
In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved and 
treatment with antihistamines and paracetamol should be considered. The infusion can be restarted 
with a reduction of the infusion rate to 50% – 25% of the rate at which the reaction occurred. 
 
In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pre-treatment should be 
considered (antihistamines and paracetamol and/or corticosteroids) and a reduction of the infusion rate 
to 50% – 25% of the rate at which the previous reaction occurred. 
 
As with any intravenous protein medicinal product, severe allergic-type hypersensitivity reactions are 
possible. If these reactions occur, immediate discontinuation of Naglazyme is recommended and 
appropriate medical treatment should be initiated. The current medical standards for emergency 
treatment are to be observed. In patients who have experienced allergic reactions during infusion with 
Naglazyme, caution should be exercised upon rechallenge; appropriately trained personnel and 
equipment for emergency resuscitation (including epinephrine) should be available during infusions. 
Severe, or potentially life-threatening hypersensitivity is a contraindication to rechallenge, if 
hypersensitivity is not controllable. See also section 4.3. 
 

Spinal or cervical cord compression 

Spinal/cervical cord compression (SCC) with resultant myelopathy is a known and serious 
complication that can be due to MPS VI. There have been post-marketing reports of patients treated 
with Naglazyme who experienced the onset or worsening of SCC requiring decompression surgery.  
Patients should be monitored for signs and symptoms of spinal/cervical cord compression (including 
back pain, paralysis of limbs below the level of compression, urinary and faecal incontinence) and 
given appropriate clinical care. 
 
Risk of Acute Cardio-respiratory Failure  
 
Caution should be exercised when administering Naglazyme to patients susceptible to fluid volume 
overload; such as in patients weighing 20 kg or less, patients with acute underlying respiratory illness, 
or patients with compromised cardiac and/or respiratory function, because congestive heart failure 
may occur.  Appropriate medical support and monitoring measures should be readily available during 
Naglazyme infusion, and some patients may require prolonged observation times that should be based 
on the individual needs of the patient (see section 4.2). 
 
Immune-mediated Reactions 
 
Type III immune complex-mediated reactions including membranous glomerulonephritis have been 
observed with Naglazyme. If immune-mediated reactions occur, discontinuation of the administration 
of Naglazyme should be considered, and appropriate medical treatment initiated.  The risks and 
benefits of re-administering Naglazyme following an immune-mediated reaction should be considered 
(see section 4.2).   
 
Sodium restricted diet  
 
This medicinal product contains 0.8 mmol (18.4 mg) sodium per vial and is administered in sodium 
chloride 9 mg/ml solution for injection (see section 6.6). To be taken into consideration by patients on 
a controlled sodium diet. 
 



5 

 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
For Naglazyme, no clinical data on exposed pregnancies are available. Animal studies do not indicate 
direct or indirect harmful effects with respect to pregnancy or embryo-foetal development (see 
section 5.3). Naglazyme should not be used during pregnancy unless clearly necessary. 
 
Breast-feeding 
It is not known whether galsulfase is excreted in milk, therefore breast-feeding should be stopped 
during Naglazyme treatment.  
 
Fertility 
Reproduction studies have been performed in rats and rabbits at doses up to 3 mg/kg/day and have 
revealed no evidence of impaired fertility or harm to the embryo or foetus due to Naglazyme. 
 
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. 
 
4.8 Undesirable effects 
 
Due to the low number of patients in clinical trials, adverse event (AE) data from all Naglazyme 
studies have been pooled and reviewed in a single, clinical trial safety analysis. 
 
All patients treated with NAGLAZYME (59/59) reported at least one AE. The majority (42/59; 71%) 
of patients experienced at least one Adverse Drug Reaction. The most common adverse reactions were 
pyrexia, rash, pruritus, urticaria, chills/rigors, nausea, headache, abdominal pain, vomiting and 
dypsnoea. Serious adverse reactions included laryngeal edema, apnoea, pyrexia, urticaria, respiratory 
distress, angioedema, asthma and anaphylactoid reaction. 
 
Infusion reactions, defined as adverse reactions occurring during Naglazyme infusions or until the end 
of the infusion day, were observed in 33 (56%) of the 59 patients treated with Naglazyme across five 
clinical studies. Infusion reactions began as early as Week 1 and as late as Week 146 of Naglazyme 
treatment, and occurred during multiple infusions though not always in consecutive weeks. Very 
common symptoms of these infusion reactions were pyrexia, chills/rigors, rash, urticaria and 
dyspnoea. Common symptoms of infusion reactions were pruritus, vomiting, abdominal pain, nausea, 
hypertension, headache, chest pain, erythema, cough, hypotension, angioedema, respiratory distress, 
tremor, conjunctivitis, malaise, bronchospasm and arthralgia. 
 
Adverse reactions are listed in Table 1 by System Organ Class. 
 
The reactions are listed following the MedDRA frequency convention. Very common adverse 
reactions are those with a frequency of 1/10. Common reactions have a frequency of 1/100 to 
<1/10. Due to the small patient population, an adverse reaction in a single patient is classified as 
common.  
 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 
Adverse reactions reported during the Post Marketing period are included at a frequency category of 
“unknown”.  
 
Overall, one case of sleep apnoea was experienced from all clinical studies. 



6 

 
Table 1: Frequency of adverse drug reactions with Naglazyme 
 

MedDRA 
System Organ Class 

MedDRA 
Preferred Term

Frequency 

Immune system disorders Anaphylaxis, shock Unknown 

Infections and infestations Pharyngitis1, gastroenteritis1 Very common 

Nervous system disorders Areflexia1, headache Very common
Tremor Common 

Paresthesia Unknown 
Eye disorders Conjunctivitis1, corneal opacity1 Very common

Cardiac disorders Bradycardia, tachycardia, cyanosis Unknown 
Ear and labyrinth disorders Ear pain1, hearing impaired1 Very common

Vascular disorders Hypertension1 Very common
Hypotension Common 

Pallor Unknown 
Respiratory, thoracic, and mediastinal

disorders 
Dyspnoea1, nasal congestion1 Very common 

Apnoea1, cough, respiratory distress, 
asthma, bronchospasm

Common 

Laryngeal oedema, hypoxia, 
tachypnoea

Unknown 

Gastrointestinal disorders Abdominal pain1, umbilical hernia1, 
vomiting, nausea

Very common 

Skin and subcutaneous tissue 
disorders 

Angioeodema1, rash1, urticaria, pruritus Very Common
Erythema Common 

General disorders and administration 
site conditions 

Pain1, chest pain1, rigors1, malaise1, 
pyrexia 

Very Common 

Musculoskeletal and Connective 
Tissue Disorders 

Arthralgia Very common 

 
1Reactions reported more frequently in the active arm of the placebo-controlled study than the placebo 
arm; frequency determined from 39 patients of the blinded Phase 3 study. 
Other reactions with known frequency were reported from 59 patients treated with Naglazyme from all 
five clinical trials. 
 
Reactions of unknown frequency were reported post-marketing. 
 
In four patients <1 year of age, the overall safety profile of a higher dose (2 mg/kg/week) did not differ 
in a clinically meaningful manner from that of the recommended 1 mg/kg/week dose, and was 
consistent with the safety profile of Naglazyme in older children. 
 
Immunogenicity 
 
Out of the 59 patients treated with Naglazyme in the clinical studies, 54 were tested for IgG 
antibodies. 53/54 patients (98%) were positive for IgG antibodies to galsulfase.  
 
A comprehensive antibody analysis based on data from three clinical studies has been carried out in 
48 patients. 



7 

 
Although a larger proportion of subjects with high total antibody titres experienced recurrent infusion 
reactions, neither frequency nor severity could be predicted based on the anti-galsulfase antibody titre. 
Likewise, antibody development is not predictive of decreased efficacy although subjects with limited 
response in endurance parameters or urinary glycosaminoglycans (GAGs) tended to have higher peak 
anti-galsulfase titres than those with good response. 
 
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 
 
Several patients have received their total dose of Naglazyme at approximately twice the recommended 
infusion rate without apparent adverse events. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code: 
A16AB08 
 
Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes 
required for the catabolism of glycosaminoglycans (GAGs). MPS VI is a heterogeneous and 
multisystemic disorder characterized by the deficiency of N-acetylgalactoasamine 4-sulfatase, a 
lysosomal hydrolase which catalyses the hydrolysis of sulfate moiety of the glycosaminoglycan, 
dermatan sulfate. Reduced or absent N-acetylgalactosamine 4-sulfatase activity results in the 
accumulation of dermatan sulfate in many cell types and tissues. 
 
The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to 
hydrolyze the accumulated substrate and to prevent further accumulation.  
 
Purified galsulfase, a recombinant form of human N-acetylgalactosamine 4-sulfatase, is a glycoprotein 
with a molecular weight of approximately 56 kD. Galsulfase is comprised of 495 amino acids after 
cleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modification sites. 
After intravenous infusion, galsulfase is rapidly removed from the circulation and taken up by cells 
into lysosomes, most likely via mannose-6 phosphate receptors. 
 
The three clinical studies performed with Naglazyme focused on assessing the systemic manifestations 
of MPS VI such as endurance, joint mobility, joint pain and stiffness, upper airway obstruction, 
manual dexterity and visual acuity.  
 
The safety and efficacy of Naglazyme was assessed in a randomised, double blind, placebo controlled, 
Phase 3 study of 39 MPS VI patients, ranging in age from 5 to 29 years. The majority of the patients 
presented with short stature, impaired endurance, and musculoskeletal symptoms. Patients who could 
walk more than 5 meters (m) but less than 250 m in 6 minutes of a 12 Minute Walk test or less than 
400 m at the 12 minute time point at baseline were enrolled in the study. 
 
Patients received either 1 mg/kg of galsulfase or placebo every week for a total of 24 weeks. The 
primary efficacy endpoint was the numbers of meters walked in 12 minutes at Week 24 compared to 
the number of meters walked at baseline. The secondary efficacy endpoints were the rate of stairs 
climbed in three minutes and the urinary glycosaminoglycan excretion of treated patients compared to 



8 

placebo at Week 24. Thirty-eight patients subsequently enrolled in an Open Label extension study 
where they received 1 mg/kg of galsulfase every week. 
 
Following 24 weeks of therapy, Naglazyme-treated patients experienced a 92 ± 40 m improvement in 
the distance walked in 12 minutes relative to placebo-treated patients (p = 0.025). Treated patients 
experienced a 5.7 stair per minute improvement in the 3 Minute Stair Climb relative to placebo-treated 
patients. Treated patients also experienced a mean decrease in urinary glycosaminoglycan excretion of 
238 ± 17.8 μg/mg creatinine ( Standard Error [SE]) following 24 weeks of treatment relative to 
placebo-treated patients. GAG results approached the normal range for age in the Naglazyme 
treatment group. 
 
In an additional Phase 4, randomised, two-dose level study, four MPS VI patients <1 year of age were 
treated at 1 or 2 mg/kg/week for 53 to 153 weeks. 
 
Although limited by the very small number of patients that were enrolled, the conclusions that can be 
drawn from this study are the following: 
 
Treatment with Naglazyme showed improvement, or lack of worsening, of facial dysmorphism. It did 
not prevent the progression of skeletal dysplasia and development of hernias and did not prevent the 
progression of corneal clouding. Growth rate remained normal over this limited follow-up period. 
Improved hearing was noted in at least one ear for all four subjects. Urinary GAG levels decreased by 
more than 70%, consistent with results in older patients. 
 
This medicinal product has been authorised under "Exceptional Circumstances". 
This means that due to the rarity of the disease it has not been possible to obtain complete information 
on this medicinal product. 
 
The European Medicines Agency will review any new information which may become available every 
year and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg/kg 
of galsulfase as a 4 hour infusion. After 24 weeks of treatment the mean ( Standard Deviation [SD]) 
maximum plasma concentration (Cmax) was 2,357 (± 1,560) ng/ml and the mean ( SD) area under the 
plasma concentration-time curve (AUC0-t) was 5,860 ( 4,184) h  ng/ml. The mean ( SD) volume of 
distribution (Vz) was 316 ( 752) ml/kg and the mean ( SD) plasma clearance (CL) was 
7.9 ( 14.7) ml/min/kg. The mean ( SD) elimination half-life (t1/2) was 22.8 ( 10.7) minutes at 
Week 24. 
 
Pharmacokinetic parameters in Phase 1 patients have remained stable over the long term (through at 
least 194 weeks). 
 
Galsulfase is a protein and is expected to be metabolically degraded through peptide hydrolysis. 
Consequently, impaired liver function is not expected to affect the pharmacokinetics of galsulfase in a 
clinically significant way. Renal elimination of galsulfase is considered a minor pathway for clearance 
(see section 4.2). 
 
5.3 Preclinical safety data 
 
Non-clinical data revealed no special hazard for humans based on conventional studies of safety 
pharmacology, single-dose toxicity, repeated-dose toxicity or on general reproductive performance or 
embryo-foetal development in rats or rabbits. Peri- and post-natal toxicity has not been investigated. 
Genotoxic and carcinogenic potential are not expected. 
 
The cause of clinical relevance of the hepatic toxicity (bile duct hyperplasia / periportal inflammation) 
seen at clinically relevant doses in the repeated dose monkey toxicity study is not known. 



9 

 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium chloride 
Sodium phosphate monobasic, monohydrate 
Sodium phosphate dibasic, heptahydrate 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vials: 3 years. 
 
Diluted solutions:  Chemical and physical in-use stability has been demonstrated for up to 4 days at 
room temperature (23C - 27C). 
 
From a microbiological safety point of view, Naglazyme should be used immediately. If not used 
immediately, in-use storage times and conditions are the responsibility of the user and should normally 
not be longer than 24 hours at 2C - 8C followed by up to 24 hours at room temperature (23C -
 27C) during administration. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C - 8°C). 
 
Do not freeze. 
 
For storage conditions of the diluted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Vial (type I glass) with a stopper (siliconized chlorobutyl rubber) and a seal (aluminium) with a flip-
off cap (polypropylene). 
 
Pack sizes: 1 and 6 vials.  
Not all package sizes may be marketed.  
 
6.6 Special precautions for disposal and other handling 
 
Each vial of Naglazyme is intended for single use only. The concentrate for solution for infusion has 
to be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion using aseptic technique. It is 
recommended that the diluted Naglazyme solution be administered to patients using an infusion set 
equipped with a 0.2 µm in-line filter. 
 
Any unused product or waste material is to be disposed of in accordance with local requirements. 
 



10 

Preparation of the Naglazyme infusion (aseptic technique is to be used) 
 
The number of vials to be diluted based on the individual patient's weight must be determined and 
removed from the refrigerator approximately 20 minutes in advance in order to allow them to reach 
room temperature. 
 
Before dilution, each vial is to be inspected for particulate matter and discolouration. The clear to 
slightly opalescent and colourless to pale yellow solution must be free of visible particles. 
 
A volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion is to be withdrawn and 
discarded from a 250 ml infusion bag equal to the total volume of Naglazyme to be added. 100 ml 
infusion bags should be considered for patients who are susceptible to fluid volume overload and 
weigh less than 20 kg; in this case the infusion rate (ml/min) should be decreased so that the total 
duration remains no less than 4 hours. When using 100 ml bags, the volume of Naglazyme may be 
added directly to the infusion bag. 
 
The volume of Naglazyme is to be slowly added to the sodium chloride 9 mg/ml (0.9%) solution for 
infusion. 
 
The solution is to be mixed gently before infusion. 
 
The solution is to be visually inspected for particulate matter prior to use. Only clear and colourless 
solutions without visible particles should be used. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
Shanbally, Ringaskiddy, 
County Cork, P43 R298 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/05/324/001 
EU/1/05/324/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 24 January 2006 
Date of latest renewal: 26 January 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
MM/YYYY 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 



11 

 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 

SUBSTANCE AND MANUFACTURING AUTHORISATION 
HOLDER RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OF THE MARKETING AUTHORISATION 

 
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE 

MARKETING AUTHORISATION HOLDER 
 

 



12 

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

 
Name and address of the manufacturer of the biological active substance 
 
BioMarin Pharmaceutical Inc. 
46 Galli Drive, Novato, CA 94949 
United States of America 
 
Name and address of the manufacturer responsible for batch release 
 
BioMarin International Limited  
Shanbally, Ringaskiddy  
County Cork, P43 R298  
Ireland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.  
 
 
B CONDITIONS OF THE MARKETING AUTHORISATION 
 
 CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 

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

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable. 
 
 OTHER CONDITIONS 
 
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in 
the Pharmacovigilance Plan. 
 
An updated Risk Management Plan should be provided as per the CHMP Guideline on Risk 
Management System for medicinal products for human use. 
 
Pharmacovigilance system 
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the 
Marketing Authorisation , is in place and functioning before and whilst the product is on the market. 
 
Risk Management Plan 
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in 
the Pharmacovigilance Plan, as agreed in version 002 of the Risk Management Plan (RMP) presented 
in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by 
the CHMP. 
 
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any 
updated RMP should be submitted at the same time as the following Periodic Safety Update Report 
(PSUR). 
 
In addition, an updated RMP should be submitted: 



13 

 When new information is received that may impact on the current Safety 
Specification,Pharmacovigilance Plan or risk minimisation activities 

 Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 
reached 

 At the request of the European Medicines Agency 
 
PSURs 
The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP. 
 
 
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING 

AUTHORISATION HOLDER 
 
The Marketing Authorisation Holder shall complete the following programme of studies within the 
specified time frame, the results of which shall form the basis of the annual reassessment of the 
benefit/risk profile. 
 
Specific Obligations: 
 

Description: 
 

Due Date 

Module 5 – Clinical  
SO2 001.3 
To evaluate the long-term safety and efficacy data from Naglazyme treatment 
a Clinical Surveillance Program (CSP) will be conducted. 
Substudies will be conducted within the CSP that will: 

1. Evaluate the effect of Naglazyme on pregnancy and lactation. 
2. Evaluate the safety and efficacy of Naglazyme in 10 children less than 

5 years of age will be treated with the 1 mg/kg dose for at least one year. 
Information will also be collected on clinical status, adverse events, 
assessments of immunogenicity and potential effects on antibody formation. 
The CSP data will be analysed at yearly intervals and results will be submitted 
as annual reports. 
Detailed clinical status information will be collected at study entry and on an 
annual basis for at least 15 years. 
Other measures (urinary GAG, antibodies) are assessed more frequently. 
Severe and serious liver toxicities will be assessed through the PSUR but also 
through analysis of these events in the CSP database.  
Subjects enrolled in the program will have urinary glycosaminoglycan and 
samples for total antibodies routinely collected as specified in the Schedule of 
Activities. Higher antibody levels (≥ 65610 Dilution Fraction) will be 
compared with the subject’s urinary GAG values with a view to assess 
potential impacts on efficacy. Samples from those subjects who have a 
consistent increase in urinary GAG values together with high antibody levels 
will have their antibody samples assessed for evidence of neutralizing 
activities.  
Samples for total antibody will be collected at specific intervals. If a physician 
suspects an IgE mediated reaction they have been advised in the protocol to 
request IgE antibody presence to be conducted by the MAH.  
The final study report under this CSP will be submitted by 31 July 2020. 

Interim results will 
be provided in the 
CSP Annual 
Reports. 
 
A brief update will 
be submitted as part 
of the Annual 
Reassessments. 
 

SOB 002 
To evaluate the long-term safety and efficacy data from Naglazyme treatment 
a Clinical Surveillance Program (CSP) will be conducted. 
Substudies will be conducted within the CSP that will: 

1. Evaluate the effect of Naglazyme on pregnancy and lactation. 
2. Evaluate the safety and efficacy of Naglazyme in 10 children less than 

5 years of age will be treated with the 1 mg/kg dose for at least one year. 

Final CSP Study 
Report: 31 July 
2020 



14 

Description: 
 

Due Date 

Information will also be collected on clinical status, adverse events, 
assessments of immunogenicity and potential effects on antibody formation 
The CSP data will be analysed at yearly intervals and results will be submitted 
as annual reports. 
Detailed clinical status information will be collected at study entry and on an 
annual basis for at least 15 years. 
Other measures (urinary GAG, antibodies) are assessed more frequently. 
Severe and serious liver toxicities will be assessed through the PSUR but also 
through analysis of these events in the CSP database.  
Subjects enrolled in the program will have urinary glycosaminoglycan and 
samples for total antibodies routinely collected as specified in the Schedule of 
Activities. Higher antibody levels (≥ 65610 Dilution Fraction) will be 
compared with the subject’s urinary GAG values with a view to assess 
potential impacts on efficacy. Samples from those subjects who have a 
consistent increase in urinary GAG values together with high antibody levels 
will have their antibody samples assessed for evidence of neutralizing 
activities.  
Samples for total antibody will be collected at specific intervals. If a physician 
suspects an IgE mediated reaction they have been advised in the protocol to 
request IgE antibody presence to be conducted by the MAH.  
The final study report under this CSP will be submitted by 31 July 2020. 
SO2 003.2 
Several measures will be implemented to assess the Naglazyme dose. Data 
collected in the post-marketing phase will also be examined to determine if a 
suitable Naglazyme maintenance dose can be recommended relative to the 
efficacy endpoints used in the clinical studies.

Interim results will 
be provided in the 
annual 
re-assessment 
reports. 



15 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



17 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Naglazyme 1 mg/ml concentrate for solution for infusion 
Galsulfase 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of solution contains 1 mg galsulfase. One vial of 5 ml contains 5 mg galsulfase. 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium chloride 
Sodium phosphate monobasic monohydrate 
Sodium phosphate dibasic heptahydrate 
Polysorbate 80 
Water for injections 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 vial of concentrate for solution for infusion 
6 vials of concentrate for solution for infusion 
5 mg/5 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



18 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
Do not freeze 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
For single use only 
Any unused solution should be discarded 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork, P43 R298 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/05/324/001  1 vial 
EU/1/05/324/002  6 vials 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
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. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
 



19 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 



20 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Clear type 1, 5 ml VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Naglazyme 1 mg/ml concentrate for solution for infusion 
Galsulfase 
Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 mg/5 ml 
 
 
6. OTHER 
 
Store in a refrigerator 
Do not freeze 



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



22 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Naglazyme 1 mg/ml concentrate for solution for infusion 
Galsulfase 

 
▼This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how 
to report side effects.  
 
 
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. 
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor. 
 
 
What is in this leaflet:  
1. What this medicine is and what it is used for 
2. What you need to know before you are given this medicine  
3. How this medicine is given 
4. Possible side effects 
5. How to store this medicine 
6. Contents of the pack and other information 
 
 
1. What this medicine is and what it is used for 
 
Naglazyme is used to treat patients with MPS VI disease (Mucopolysaccharidosis VI).  
 
People with MPS VI disease have either a low level, or no level, of an enzyme called 
N-acetylgalactosamine 4-sulfatase, which breaks down specific substances (glycosaminoglycans) in 
the body. As a result, these substances do not get broken down and processed by the body as they 
should. They accumulate in many tissues in the body, which causes the symptoms of MPS VI. 
 
How this medicine works 
 
This medicine contains a recombinant enzyme called galsulfase. This can replace the natural enzyme 
which is lacking in MPS VI patients.  Treatment has been shown to improve walking and stair-
climbing ability, and to reduce the levels of glycosaminoglycans in the body.  This medicine may 
improve the symptoms of MPS VI. 
 
 
2. What you need to know before you are given this medicine  
 
You must not receive this medicine 
- If you have experienced severe or life-threatening allergic (hypersensitive) reactions to 

galsulfase or any of the other ingredients of Naglazyme and re-administration of the medicine 
was not successful. 

 
Warnings and precautions 
- If you are treated with Naglazyme, you may develop infusion-associated reactions. An infusion 

associated reaction is any side effect occurring during the infusion or until the end of the 
infusion day (see section 4 “Possible Side Effects”). When you experience such a reaction, you 
should immediately contact your doctor. 



23 

-  If you have an allergic reaction your doctor may slow down, or stop, your infusion.  Your doctor 
may also give you additional medicines to manage any allergic reactions. 

- If you have a fever, or if you are having difficulty breathing before this medicine is given, talk 
with your doctor about delaying your Naglazyme infusion. 

- If you have an underlying heart condition, please inform your doctor at any point while being 
treated with Naglazyme. They may adjust your infusion based on this information. 

-  This medicine has not been tested in patients with kidney or liver problems. Talk to your doctor 
if you have kidney or liver insufficiency. 

- Please talk to your doctor if you experience muscle pain, numbness in your arms or legs, or any 
bowel or bladder problems as these may be caused by pressure on your spinal cord. 

 
Other medicines and Naglazyme 
Please tell your doctor if you are taking or have recently taken any other medicines, including 
medicines obtained without a prescription. 
 
Pregnancy and breast-feeding 
Naglazyme should not be given during pregnancy unless clearly necessary. Ask your doctor or 
pharmacist for advice before taking any medicine.  It is not known whether galsulfase is excreted in 
milk, therefore breast-feeding should be stopped during Naglazyme treatment. Ask your doctor or 
pharmacist for advice before taking any medicine. 
 
Driving and using machines 
No studies on the effects on the ability to drive and use machines have been performed. 
 
This medicine contains Sodium 
Each 5 ml vial contains 0.8 mmol (18.4 mg) of sodium and is administered in sodium chloride 9 
mg/ml solution for injection. To be taken into consideration by patients on a controlled sodium diet. 
 
 
3. How this medicine is given 
 
Your doctor or nurse will administer Naglazyme to you. 
The dose you receive is based on your body weight.  The recommended dose is 1 mg/kg body weight 
administered once every week through a drip into a vein (by intravenous infusion). Each infusion will 
take approximately 4 hours. For the first hour the infusion rate will be slow (approximately 2.5% of 
the total solution), with the remaining volume (approximately 97.5%) being taken over the next 3 
hours. 
 
If you are given more Naglazyme than you should 
Naglazyme is administered under the supervision of a nurse or doctor, he or she will check that the 
correct dose has been given and act accordingly if necessary. 
 
If you forget to take this medicine 
If you have missed a Naglazyme infusion, please contact your doctor.  If you have any further 
questions on the use of this medicine, ask your doctor. 
 
 
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 
associated reactions”). The most serious side effects were swollen face and fever (very common); 
longer than normal gaps between breaths, difficulty breathing, asthma and hives (common); and 
swelling of the tongue and throat, and serious allergic reaction to this medicine (unknown frequency). 



24 

If you experience any reaction like this, please tell your doctor immediately. You may need to be 
given additional medicines to prevent an allergic reaction (e.g. antihistamines and/or corticosteroids) 
or to reduce fever (antipyretics). 
The most common symptoms of infusion associated reactions include fever, chills, rash, hives and 
shortness of breath. 
 
Very common side effects (these may affect more than 1 in 10 people):  
 

 Sore throat 
 Gastroenteritis 
 Poor reflexes 
 Headache 
 Inflammation of the eye 
 Cloudy eyes 
 Poor hearing 
 High blood pressure 
 

 Nasal congestion 
 Bulging belly button 
 Vomiting 
 Nausea 
 Itching 
 Pain (including ear, abdominal, joint, chest 

pain) 
 Malaise  

 
Common side effects (these may affect up to 1 in 10 people):  
 

 Tremor 
 Low blood pressure 
 Cough 

 Wheezing 
 Skin redness 

 
 
Other side effects with an unknown frequency:  
 

 Shock 
 Tingling 
 Decreased heart rate 
 Increased heart rate 

 Bluish skin  
 Skin paleness 
 Low blood-oxygen 
 Rapid breathing 

 
If you get any of these symptoms, or other symptoms not listed in this leaflet, tell your doctor 
immediately. 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 this medicine 
 
Keep out of the sight and reach of children. 
 
Do not take use this medicine after the expiry date which is stated on the vial after EXP. The expiry 
date refers to the last day of that month. 
 
Unopened vials:  
Store in a refrigerator (2C - 8C).  
 
Do not freeze. 
 
Diluted solutions:  
Chemical and physical in-use stability has been demonstrated for up to 4 days at room temperature 
(23C - 27C). 
 
From a microbiological safety point of view, the product is to be used immediately. If not used 
immediately, in-use storage times and conditions are the responsibility of the user and must normally 
not be longer than 24 hours at 2C - 8C followed by up to 24 hours at room temperature 
(23C - 27C) during administration. 



25 

 
Do not take Naglazyme if it contains visible particles.  
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Naglazyme contains 
 
- The active substance is galsulfase. One ml of Naglazyme contains 1 mg galsulfase. One vial of 

5 ml contains 5 mg galsulfase. Galsulfase is recombinant human N-acetylgalactosamine 
4-sulfatase produced by genetically engineered Chinese Hamster Ovary (CHO) cells. 

- The other ingredients are: sodium chloride, sodium phosphate monobasic, monohydrate, sodium 
phosphate dibasic, heptahydrate, polysorbate 80, water for injections. 

 
What Naglazyme looks like and contents of the pack 
 
Naglazyme is supplied as a concentrate for solution for infusion. The clear to slightly opalescent and 
colourless to pale yellow concentrate must be free of visible particles. The solution must be diluted 
further before it can be infused.  
 
Pack sizes: 1 and 6 vials. Not all package sizes may be marketed.  
 
Marketing Authorization Holder  
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork, P43 R298 
Ireland 
 

Manufacturer  
BioMarin International Limited  
Shanbally, Ringaskiddy  
County Cork, P43 R298  
Ireland 

 
This leaflet was last revised in MM/YYYY 
 
This medicine has been authorised under “exceptional circumstances”. 
 
This means that because of the rarity of this disease it has been impossible to get complete information 
on this medicine. 
 
The European Medicines Agency will review any new information on the medicine every year and this 
leaflet will be updated as necessary. 
 
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 medical or healthcare professionals only: 
 
Naglazyme should not be mixed with other medicinal products in the same infusion, except for those 
mentioned below. 
 
Each vial of Naglazyme is intended for single use only. The concentrate for solution for infusion has 
to be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion using aseptic technique. It is 
recommended that the diluted Naglazyme solution be administered to patients using an infusion set 
equipped with a 0.2 µm in-line filter. 
 
Any unused product or waste material is to be disposed of in accordance with local requirements. 



26 

 
Preparation of the Naglazyme Infusion (Use Aseptic Technique) 
 
The number of vials to be diluted based on the individual patient's weight must be determined and 
removed from the refrigerator approximately 20 minutes in advance in order to allow them to reach 
room temperature. 
 
Before dilution, each vial is to be inspected for particulate matter and discolouration. The clear to 
slightly opalescent and colourless to pale yellow solution must be free of visible particles.  
 
A volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion is to be withdrawn and 
discarded from a 250 ml infusion bag equal to the total volume of Naglazyme to be added. 100 ml 
infusion bags should be considered for patients who are susceptible to fluid volume overload and 
weigh less than 20 kg; in this case the infusion rate (ml/min) should be decreased so that the total 
duration remains no less than 4 hours. When using 100 ml bags, the volume of Naglazyme may be 
added directly to the infusion bag. 
 
The volume of Naglazyme is to be slowly added to the sodium chloride 9 mg/ml (0.9%) solution for 
infusion. 
 
The solution is to be mixed gently for infusion. 
 
The solution is to be visually inspected for particulate matter prior to use. Clear and colourless 
solutions without visible particles should be used. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE ANDMANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCHRELEASE
	B CONDITIONS OF THE MARKETING AUTHORISATI
	C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETINGAUTHORISATION HOLDER
	A. LABELLING
	B. PACKAGE LEAFLET