Vimizim

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 
 
Vimizim 1 mg/ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of solution contains 1 mg elosulfase alfa*. Each vial of 5 ml contains 5 mg elosulfase alfa. 
 
*Elosulfase alfa is a recombinant form of human N-acetylgalactosamine-6-sulfatase (rhGALNS) and 
is produced in Chinese Hamster Ovary cell culture by recombinant DNA technology. 
 
Excipients with known effect: 
 
Each 5 ml vial contains 8 mg sodium and 100 mg sorbitol (E420). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (Sterile concentrate). 
A clear to slightly opalescent and colourless to pale yellow solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Vimizim is indicated for the treatment of mucopolysaccharidosis, type IVA (Morquio A Syndrome, 
MPS IVA) in patients of all ages.  
 
4.2 Posology and method of administration 
 
Treatment should be supervised by a physician experienced in the management of patients with 
MPS IVA or other inherited metabolic diseases. Administration of Vimizim should be carried out by 
an appropriately trained healthcare professional with the ability to manage medical emergencies. 
Home administration under the supervision of an appropriately trained healthcare professional may be 
considered for patients who are tolerating their infusions well. 
 
Posology  
 
The recommended dose of elosulfase alfa is 2 mg/kg of body weight administered once a week. The 
total volume of the infusion should be delivered over approximately 4 hours (see Table 1).  
 
Because of the potential for hypersensitivity reactions with elosulfase alfa, patients should receive 
antihistamines with or without antipyretics 30 to 60 minutes prior to start of infusion (see section 4.4). 
 



 

3 

Special populations 
 
Elderly patients (≥ 65 years old) 
 
The safety and efficacy of Vimizim in patients older than 65 years has not been established, and no 
alternative treatment regimen can be recommended in these patients. It is not known whether elderly 
patients respond differently from younger patients. 
 
Paediatric population 
 
The posology in the paediatric population is the same as in adults. Currently available data are 
described in section 4.8 and section 5.1. 
 
Method of administration 
 
For intravenous infusion only. 
 
Patients weighing less than 25 kg should receive a total volume of 100 ml. When diluted in 100 ml, the 
initial infusion rate should be 3 ml/hr. The infusion rate may be increased as tolerated, every 
15 minutes as follows: first increase the rate to 6 ml/hr, then increase the rate every 15 minutes by 
6 ml/hr increments until a maximum rate of 36 ml/hr is reached.  
 
Patients weighing 25 kg or more should receive a total volume of 250 ml. When diluted in 250 ml, the 
initial infusion rate should be 6 ml/hr. The infusion rate may be increased as tolerated, every 
15 minutes as follows: first increase the rate to 12 ml/hr, then increase the rate every 15 minutes by 
12 ml/hr increments until a maximum rate of 72 ml/hr is reached. 
 

Table 1: Recommended infusion volumes and rates*  
Patient 
weight 

(kg) 

Total 
infusion 
volume 

(ml) 

Step 1 
Initial 

infusion 
rate 0-15 
minutes 
(ml/hr) 

Step 2 
15-30 

minutes 
(ml/hr) 

Step 3 
30-45 

minutes 
(ml/hr) 

Step 4 
45-60 

minutes 
(ml/hr) 

Step 5 
60-75 

minutes 
(ml/hr) 

Step 6 
75-90 

minutes 
(ml/hr) 

Step 7 
90+ 

minutes
(ml/hr) 

< 25 100 3 6 12 18 24 30 36
≥ 25 250 6 12 24 36 48 60 72

* Infusion rate may be increased as tolerated by patient.  
 
For instructions for dilution of the medicinal product prior to administration, see section 6.6. 
 
4.3 Contraindications 
 
Life-threatening hypersensitivity (anaphylactic reaction) to the active substance or to any of the 
excipients listed in section 6.1 (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Anaphylaxis and severe allergic reactions 
 
Anaphylaxis and severe allergic reactions have been reported in clinical studies. Therefore, appropriate 
medical support must be readily available when elosulfase alfa is administered. If these reactions 
occur, immediately stop the infusion and initiate appropriate medical treatment.  The current medical 
standards for emergency treatment are to be followed. For patients who have experienced allergic 
reactions during infusion, caution should be exercised upon re-administration. 
 



 

4 

Infusion reactions 
 
Infusion reactions (IRs) were the most commonly observed adverse reactions in clinical studies. IRs 
may include allergic reactions. Patients should receive antihistamines with or without antipyretics 
prior to infusion (see section 4.2). Management of IRs should be based on the severity of the reaction 
and include slowing or temporary interruption of the infusion and/or administration of additional 
antihistamines, antipyretics, and/or corticosteroids. If severe IRs occur, immediately stop the infusion 
and initiate appropriate treatment. Re-administration after a severe reaction should be carried out with 
caution and close monitoring by the treating physician. 
 
Spinal/Cervical cord compression 
 
In clinical studies, spinal/cervical cord compression (SCC) was observed both in patients receiving 
Vimizim and patients receiving placebo. Patients should be monitored for signs and symptoms of SCC 
(including back pain, paralysis of limbs below the level of compression, urinary and faecal 
incontinence) and given appropriate clinical care. 
 
Sodium restricted diet 
 
This medicinal product contains 8 mg sodium per vial, equivalent to 0.4% of the WHO recommended 
maximum daily intake of 2 g sodium for an adult, and is administered in sodium chloride 9 mg/ml 
(0.9%) solution for infusion (see section 6.6). 
 
Sorbitol (E 420) 
 
This medicinal product contains 100 mg sorbitol in each vial which is equivalent to 40 mg/kg.  
Patients with hereditary fructose intolerance (HFI) must not be given this medicinal product unless 
strictly necessary. 
 
Babies and young children (below 2 years of age) may not yet be diagnosed with hereditary fructose 
intolerance (HFI).  Medicinal products containing sorbitol/fructose given intravenously may be life-
threatening. The treatment benefit to the child compared to the associated risks must be fully evaluated 
prior to treatment.   
 
A detailed history with regard to HFI symptoms has to be taken for each patient prior to being given 
this medicinal product. 
 
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 
 
There are no data on the use of Vimizim in pregnant women.  
 
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryo-
foetal development (see section 5.3). These studies however, are of limited relevance. As a 
precautionary measure, it is preferable to avoid the use of Vimizim during pregnancy, unless clearly 
necessary.  
 
Breast-feeding 
 
Available reproductive data in animals have shown excretion of elosulfase alfa in milk. It is not known 
whether elosulfase alfa is excreted in human breast milk, but systemic exposure via breast milk is not 



 

5 

expected. Due to lack of human data, Vimizim should only be administered to breast-feeding woman 
if the potential benefit is considered to outweigh the potential risk to the infant. 
 
Fertility 
 
No impairment of fertility has been observed in nonclinical studies (see section 5.3) with elosulfase 
alfa. 
 
4.7 Effects on ability to drive and use machines 
 
Vimizim has minor influence on the ability to drive and use machines. Dizziness was reported during 
Vimizim infusions; if dizziness occurs after the infusion, the ability to drive and use machines may be 
affected.  
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The assessment of adverse reactions is based on the exposure of 176 patients with MPS IVA, ages 5 to 
57 years old to 2 mg/kg elosulfase alfa once a week (n=58), 2 mg/kg elosulfase alfa once every other 
week (n=59), or placebo (n=59) in a randomised, double-blind, placebo-controlled study. 
 
The majority of adverse reactions in clinical studies were IRs, which are defined as reactions occurring 
after initiation of infusion until the end of the day following the infusion. Serious IRs were observed in 
clinical studies and included anaphylaxis, hypersensitivity and vomiting. The most common symptoms 
of IRs (occurring in ≥ 10% of patients treated with Vimizim and ≥ 5% more when compared to 
placebo) were headache, nausea, vomiting, pyrexia, chills and abdominal pain. IRs were generally 
mild or moderate, and the frequency was higher during the first 12 weeks of treatment and tended to 
occur less frequently with time. 
 
Tabulated list of adverse reactions 
 
The data in Table 2 below describes adverse reactions from clinical studies in patients treated with 
Vimizim.  
 
Frequencies are defined as: 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 available data). Within each frequency grouping, adverse reactions are presented in 
order of decreasing seriousness.  
 

Table 2: Adverse reactions in patients treated with Vimizim 
 

MedDRA 
System organ class 

MedDRA 
Preferred term 

Frequency 

Immune system disorders Anaphylaxis Uncommon 
Hypersensitivity Common 

Nervous system disorders 
 

Headache Very common 
Dizziness Very common 

Respiratory, thoracic, and 
mediastinal disorders 

Dyspnoea Very common 

Gastrointestinal disorders Diarrhoea, vomiting, 
oropharyngeal pain, upper 
abdominal pain, abdominal pain, 
nausea

Very common 

Musculoskeletal and connective Myalgia Common 



 

6 

tissue disorders Chills Very common 
General disorders and 
administration site conditions 

Pyrexia Very common 

 
Description of selected adverse reactions 
 
Immunogenicity 
 
All patients developed antibodies to elosulfase alfa in clinical studies. Approximately 80% of patients 
developed neutralizing antibodies capable of inhibiting the elosulfase alfa from binding to the cation-
independent mannose-6-phosphate receptor. Sustained improvements in efficacy measures and 
reductions in urine keratan sulphate (KS) over time were observed across studies, despite the presence 
of anti elosulfase alfa antibodies. No correlations were found between higher antibody titres or 
neutralizing antibody positivity and reductions in efficacy measurements or occurrence of anaphylaxis 
or other hypersensitivity reactions. IgE antibodies against elosulfase alfa were detected in ≤ 10% of 
treated patients and have not consistently been related to anaphylaxis or other hypersensitivity 
reactions and/or treatment withdrawal.  
 
Paediatric population 
 
In patients < 5 years of age, the overall safety profile of Vimizim at 2 mg/kg/week was consistent with 
the safety profile of Vimizim observed in older children. 
 
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 
 
In clinical studies, doses of elosulfase alfa were explored up to 4 mg/kg per week and no specific signs 
or symptoms were identified following the higher doses. No differences in the safety profile were 
observed. For management of adverse reactions, see sections 4.4 and 4.8.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes.  ATC code: 
A16AB12.  
 
Mechanism of action  
 
Mucopolysaccharidoses comprises a group of lysosomal storage disorders caused by the deficiency of 
specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). MPS IVA is 
characterised by the absence or marked reduction in N-acetylgalactosamine-6-sulfatase activity. The 
sulfatase activity deficiency results in the accumulation of the GAG substrates, KS and chondroitin 6 
sulphate (C6S), in the lysosomal compartment of cells throughout the body. The accumulation leads to 
widespread cellular, tissue, and organ dysfunction. Elosulfase alfa is intended to provide the 
exogenous enzyme N-acetylgalactosamine-6-sulfatase that will be taken up into the lysosomes and 
increase the catabolism of the GAGs KS and C6S. Enzyme uptake by cells into lysosomes is mediated 
by cation independent mannose-6-phosphate receptors leading to restored GALNS activity and 
clearance of KS and C6S. 



 

7 

 
Clinical efficacy and safety 
 
Clinical studies performed with Vimizim assessed the impact of treatment on the systemic 
manifestations of MPS IVA in various domains including endurance, respiratory function, growth 
velocity, and mobility, as well as urine KS. 
 
A total of 235 patients with MPS IVA were enrolled and exposed to Vimizim in six clinical studies.  
 
The safety and efficacy of Vimizim was assessed in a randomised, double-blind, placebo-controlled, 
Phase 3 clinical study of 176 patients with MPS IVA, ranging in age from 5 to 57 years. The majority 
of the patients presented with short stature, impaired endurance, and musculoskeletal symptoms. 
Patients who could walk more than 30 meters (m) but less than 325 m in a 6 Minute Walk Test 
(MWT) at baseline were enrolled in the study. 
 
Patients received elosulfase alfa 2 mg/kg every week (n=58) or 2 mg/kg every other week (n=59), or 
placebo (n=59) for a total of 24 weeks. All patients were treated with antihistamines prior to each 
infusion. The primary endpoint was the change from baseline in the 6 MWT distance compared to 
placebo at Week 24. The secondary endpoints were the change from baseline in the 3 Minute Stair 
Climb Test (MSCT) and urine KS levels at Week 24. A total of 173 patients subsequently enrolled in 
an extension study in which patients received 2 mg/kg of elosulfase alfa every week or 2 mg/kg every 
other week, and then all were switched to 2 mg/kg every week upon availability of the Week 24 
results. 
 
The primary and secondary endpoints were evaluated at Week 24 (see Table 3). The modelled 
treatment effect in the distance walked in 6 minutes, compared to placebo, was 22.5 m (CI95, 4.0, 40.9; 
p=0.0174) for the 2 mg/kg per week regimen. The modelled treatment effect in stairs climbed per 
minute, compared to placebo, was 1.1 stairs/minute (CI95, -2.1, 4.4; p=0.4935) for the 2 mg/kg per 
week regimen. The modelled treatment effect for the percent change in urine KS, compared to 
placebo, was -40.7 % (CI95, -49.0, -32.4; p<0.0001) for the 2 mg/kg per week regimen. The difference 
was greatest between the placebo group and the weekly treatment group for all endpoints. The results 
from the every other week regimen in the distance walked in 6 minutes or in stairs climbed per minute 
were comparable to placebo.  
 

Table 3: Results from placebo-controlled clinical study at 2 mg per kg per week 
 

 
 

Vimizim Placebo Vimizim vs. 
placebo 

Baselin
e 

Week 
24 

Chang
e 

Baselin
e 

Week 24 Change
Difference in 

changes N 58 57* 57 59 59 59
6-Minute walk test (meters) 
Mean

  
 SD 

203.9  
±76.32 

 
 

243.3 
±83.53 

 
 

36.5  
±58.49 

 
 

211.9  
±69.88 

 
 

225.4  
±83.22 

 
 

13.5  
±50.63 

 
 

 

  Model-based mean‡
(95%CI) 
p-value 

22.5  
(CI95, 4.0, 40.9) 

(p = 0.0174) 
3-Minute stair climb test (stairs/minute) 



 

8 

Mean
  
 SD 

29.6 
 ±16.44 
 

34.9  
± 18.39 

 
 

4.8  
± 8.06 

 
 

30.0  
± 14.05 
 

 

33.6 
 ± 18.36 

 
 

3.6  
± 8.51 

 
 

 

  Model-based mean‡
(95%CI) 
p-value 

1.1  
(CI95, -2.1, 4.4) 

(p = 0.4935)  
* One patient in the Vimizim group dropped out after 1 infusion  
‡ Model-based mean of Vimizim versus placebo, adjusted for baseline 

 
In additional extension studies, patients receiving elosulfase alfa 2 mg/kg every week, showed 
maintenance of initial improvement in endurance and sustained reduction of urinary KS up to 
156 weeks.  
 
Paediatric population  
 
It is important to initiate treatment as early as possible.   
 
The majority of patients who received Vimizim during clinical studies were in the paediatric and 
adolescent age range (5 to 17 years).  In an open-label study, 15 paediatric patients with MPS IVA 
under the age of 5 years (9 months to <5 years) received 2 mg/kg of Vimizim once a week for 
52 weeks. Patients continued a long-term follow-up observational study for at least another 52 weeks, 
for a total of 104 weeks. Safety and pharmacodynamic results in these patients are consistent with 
results observed in the first 52 weeks (see section 4.8). The baseline mean (±SD) normalised standing 
height z-score was - 1.6 (±1.61). After the first 52 weeks of treatment the normalised standing height 
z-score was -1.9 (±1.62). At Week 104 mean (±SD) normalised standing height z-score was -3.1 (± 
1.13). 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with  
Vimizim in one or more subsets of the paediatric population in MPS IVA. See section 4.2 for 
information on paediatric use.  
 
5.2  Pharmacokinetic properties 
 
The pharmacokinetic parameters of elosulfase alfa were evaluated in 23 patients with MPS IVA who 
received weekly intravenous infusions of 2 mg/kg of elosulfase alfa over approximately 4 hours for 
22 weeks and the parameters at Week 0 and Week 22 were compared. At Week 22, the mean AUC0-t 
and Cmax increased by 181% and 192%, respectively, when compared to Week 0 
 

Table 4: Pharmacokinetic properties 
 

Pharmacokinetic parameter 
Week 0 

Mean (SD) 
Week 22  

Mean (SD) 
AUC0-t, minute • µg/ml* 238 (100) 577 (416) 
Cmax, µg/ml† 1.49 (0.534) 4.04 (3.24) 
CL, ml/minute/kg‡ 10.0 (3.73) 7.08 (13.0) 
t1/2, minute§ 7.52 (5.48) 35.9 (21.5) 
Tmax, minute¶ 172 (75.3) 202 ( 90.8) 

* AUC0-t, area under the plasma concentration-time curve from time zero to the time of last measurable 
concentration;  

† Cmax, observed maximum plasma concentration; 
‡ CL, total clearance of elosulfase alfa after intravenous administration;  
§ t1/2, elimination half-life; 
¶ Tmax, time from zero to maximum plasma concentration 
 
 
 



 

9 

Biotransformation 
 
Elosulfase alfa 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 elosulfase alfa.  
 
Elimination 
 
Renal elimination of elosulfase alfa is considered a minor pathway for clearance. Mean half-life (t1/2) 
increased from 7.52 minutes at Week 0 to 35.9 minutes at Week 22. Male and female patients had 
comparable elosulfase alfa clearance, and clearance did not trend with age or weight at week 22. 
Impact of antibodies on elosulfase alfa pharmacokinetics was assessed. No association was apparent 
between the total antibody titre and elosulfase clearance. However, patients with positive neutralizing 
antibodies responses had decreased total clearance (CL) values and prolonged t1/2. Despite the 
alteration of the pharmacokinetics profile, presence of neutralizing antibodies did not affect 
pharmacodynamics, efficacy, or safety of the patients who were treated with elosulfase alfa. No 
accumulation of elosulfase alfa in plasma was evident following weekly dosing 
 
5.3 Preclinical safety data 
 
Non-clinical data revealed no special hazard for humans based on conventional studies of safety 
pharmacology evaluating central nervous, respiratory and cardiovascular systems, single-dose and 
repeated-dose toxicity in rats and monkeys or fertility and embryo-foetal development in rats or 
rabbits. The evaluation of the peri- and postnatal development study in rats is hampered due to 
subsequent administration of DPH, and therefore of limited relevance. 
 
Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic 
potential have not been performed with elosulfase alfa. Reproduction studies have been performed in 
rats at doses up to 10 times the human dose and have revealed no evidence of impaired fertility or 
reproductive performance. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium acetate trihydrate 
Sodium dihydrogen phosphate monohydrate 
Arginine hydrochloride 
Sorbitol (E 420) 
Polysorbate 20 
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 
 
3 years 
 
After dilution 
Chemical and physical in-use stability has been demonstrated for up to 24 hours at 2C – 8C followed 
by up to 24 hours at 23C – 27C. 
 
From a microbiological safety point of view, the diluted solution should be used immediately. If not 
used immediately, in-use storage times and conditions are the responsibility of the user and should 



 

10 

normally not be longer than 24 hours at 2C – 8C followed by up to 24 hours at 23C – 27C during 
administration. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C). Do not freeze. 
 
Store in the original package in order to protect from light. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
Clear glass vial (Type I) with a butyl rubber stopper and a flip-off crimp seal (aluminium) with a 
plastic cap. 
 
Pack sizes: 1 vial  
 
6.6 Special precautions for disposal and other handling 
 
Each vial of Vimizim is intended for single use only. Vimizim has to be diluted with sodium chloride 
9 mg/ml (0.9 %) solution for infusion using aseptic technique. The diluted solution is administered to 
patients using an infusion set. An infusion set equipped with an in-line 0.2 μm filter can be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Preparation of the Vimizim infusion  
 
Aseptic technique is to be used.  
 
Vimizim must be diluted prior to administration.  
 
The number of vials to be diluted is based on the individual patient's weight. The recommended dose is 
2 mg per kg. 
 

1. The number of vials to be diluted based on the individual patient’s weight and the 
recommended dose of 2 mg/kg is determined, using the following calculation: 
 Patient weight (kg) multiplied by 2 (mg/kg) = Patient dose (mg) 
 Patient dose (mg) divided by 1 (mg/ml concentrate of Vimizim) = Total number of ml of 

Vimizim 
 Total amount (ml) Vimizim divided by 5 ml per vial = Total number of vials 

2. The calculated total number of vials is rounded up to the next whole vial. The appropriate 
number of vials is removed from the refrigerator. Do not heat or microwave vials.  Do not 
shake vials. 

3. An infusion bag containing sodium chloride 9 mg/ml (0.9 %) solution for infusion is obtained 
suitable for intravenous administration. The total volume of the infusion is determined by the 
patient’s body weight.  
 Patients weighing less than 25 kg should receive a total volume of 100 ml.  
 Patients weighing 25 kg or more should receive a total volume of 250 ml.  

4. Before withdrawing Vimizim from the vial, each vial is visually inspected for particulate 
matter and discoloration. Because this is a protein solution, slight flocculation (thin translucent 
fibres) may occur. The Vimizim solution should be clear to slightly opalescent and colourless 
to pale yellow. Do not use if the solution is discoloured or if there is particulate matter in the 
solution. 

5. A volume of the sodium chloride 9 mg/ml (0.9 %) solution for infusion is to be withdrawn and 
discarded from the infusion bag, equal to the volume of Vimizim concentrate to be added. 



 

11 

6. The calculated volume of Vimizim from the appropriate number of vials is slowly withdrawn 
using caution to avoid excessive agitation.  

7. Vimizim is slowly added to the infusion bag using care to avoid agitation.  
8. The infusion bag is gently rotated to ensure proper distribution of Vimizim. Do not shake the 

solution. 
9. The diluted solution is administered to patients using an infusion set. An infusion set equipped 

with an in-line 0.2µm filter can be used. 
 
 

7. MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork, P43 R298 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/914/001  
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  28 April 2014 
Date of last renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
MM/YYYY 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

 



 

12 

 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE 
FOR BATCH RELEASE  

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



 

13 

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

 
Name and address of the manufacturer of the biological active substance 
 
BioMarin Pharmaceutical, Inc. 
Galli Drive Facility 
46 Galli Drive 
Novato, CA 94949 
USA 
 
BioMarin International Limited  
Shanbally, Ringaskiddy, Co. Cork  
Ireland  
P43 R298 
 
Name and address of the manufacturer responsible for batch release 
 
BioMarin International Limited 
Shanbally, Ringaskiddy, Co. Cork 
Ireland 
P43 R298 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

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

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

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

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

 
 Additional risk minimisation measures 



 

14 

 
Prior to launch in each Member State, the Marketing Authorisation Holder MAH shall agree the 
content and format of the educational programme with the national competent authority. The 
Marketing Authorisation Holder (MAH) should ensure that, at launch, all Healthcare Professionals 
who are expected to use and/or prescribe Vimizim are provided with an Educational pack. 
 
The educational pack should contain the following: 
• Summary of Product Characteristics and Patient Information Leaflet  
• Educational material for Healthcare Professionals 
 
The educational material for Healthcare Professionals should be a step by step dosing and 
administration guide that includes information on the following key elements: 
• the calculation of the dose and of the volume of infusion 
• the calculation of the infusion rate  
• the risk of anaphylaxis and of severe allergic reactions and the measures necessary to minimise 

it: 
o all patients should receive antihistamines with or without antipyretics 30–60 

minutes prior to the start of infusion 
o appropriate medical support should be readily available when VIMIZIM® is 

administered 
o the need to immediately stop the infusion and initiate appropriate medical 

treatment if these reactions occurred 
 
 Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
Set up a MPS IVA disease Registry to assess the long term safety and efficacy of 
elosulfase alfa. 

Submission of 
final study 
report: 
 
March 2025 
 

 

 



 

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 
 
Vimizim 1 mg/ml concentrate for solution for infusion 
elosulfase alfa 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 5 mg elosulfase alfa in 5 ml of solution (1 mg/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium acetate trihydrate; 
Sodium dihydrogen phosphate monohydrate; 
Arginine hydrochloride; 
Sorbitol (E 420); 
Polysorbate 20; 
Water for injections; 
See leaflet for further information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
concentrate for solution for infusion 
1 vial 
5 mg/5 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only 
Read the package leaflet before use.  
Intravenous use after dilution 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 

18 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
Do not freeze 
Store in the original package in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
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/1/14/914/001 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
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 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 
 
 



 

19 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
5 ml VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Vimizim 1 mg/ml sterile concentrate 
elosulfase alfa 
IV use after dilution 
 
 
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 
 



 

20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



 

21 

Package leaflet: Information for the user 
 

Vimizim 1 mg/ml concentrate for solution for infusion 
elosulfase alfa 

 
▼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 you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
 
What is in this leaflet 
1. What Vimizim is and what it is used for 
2. What you need to know before you are given Vimizim 
3. How Vimizim is given 
4. Possible side effects 
5. How to store Vimizim 
6. Contents of the pack and other information 
 
 
1. What Vimizim is and what it is used for 
 
Vimizim contains an enzyme called elosulfase alfa, which belongs to a group of medicines known as 
enzyme replacement therapies. It is used to treat adults and children with mucopolysaccharidosis 
type IVA (MPS IVA disease, also known as Morquio A Syndrome).  
 
People with MPS IVA disease either lack completely or do not have enough N-acetylgalactosamine-6-
sulfatase, an enzyme which breaks down specific substances in the body such as keratan sulphate, 
which are found in many tissues of the body, including cartilage and bone. As a result, these 
substances do not get broken down and processed by the body as they should. They accumulate in the 
tissues interfering with their normal function and causing the symptoms of MPS IVA, such as 
difficulty walking, trouble breathing, short height, and hearing loss. 
 
How Vimizim works 
This medicine replaces the natural enzyme N-acetylgalactosamine-6-sulfatase which is lacking in 
MPS IVA patients. Treatment has been shown to improve walking and to reduce the levels of keratan 
sulphate in the body. This medicine may improve the symptoms of MPS IVA. 
 
 
2. What you need to know before you are given Vimizim 
 
You must not receive Vimizim 
- if you have experienced life-threatening allergic reactions to elosulfase alfa or any of the other 

ingredients of this medicine (listed in section 6).  
 



 

22 

Warnings and precautions 
- If you are treated with Vimizim, you may develop infusion reactions. An infusion reaction is any 

side effect, including an allergic reaction, occurring during the infusion or within a day following 
infusion (see section 4). If you experience such a reaction, you should immediately contact your 
doctor.  

- If you have an allergic reaction during your infusion your doctor may slow down, or stop your 
infusion. Your doctor may also give you additional medicines to manage any allergic reactions 
(e.g. antihistamines and/or corticosteroids). 

- If you experience back pain, numbness in your arms or legs, or lack of control over passing urine 
or stools, you should immediately contact your doctor. These problems can be a part of the 
disease and may be caused by pressure on your spinal cord. 

 
Other medicines and Vimizim 
Please tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
Pregnancy, breast-feeding and fertility 
You should not receive Vimizim during pregnancy unless clearly necessary. It is not known whether 
Vimizim is excreted in breast milk. Discuss with your doctor if the benefits of taking Vimizim are 
greater than the potential risk to your newborn while breast-feeding. It is not known if Vimizim 
impacts human fertility. No effect on fertility was observed in animals.   
 
Driving and using machines 
Dizziness was reported in some patients during the Vimizim infusion. Tell your doctor if you feel 
dizzy after your infusion, especially before driving or using any machine where dizziness might be 
dangerous. 
 
Vimizim contains sodium and sorbitol (E 420) 
This medicine contains 8 mg sodium (main component of cooking/table salt) in each 5 ml vial. This is 
equivalent to 0.4 % of the recommended daily dietary intake of sodium for an adult. 
 
This medicine contains 100 mg sorbitol in each 5 ml vial which is equivalent to 40 mg/kg.  
Sorbitol is a source of fructose. If you (or your child) have hereditary fructose intolerance (HFI), a rare 
genetic disorder, you (or your child) must not receive this medicine unless discussed with your doctor. 
Patients with HFI cannot break down fructose, which may cause serious side effects.  
You must tell your doctor before receiving this medicine if you (or your child) have HFI or if your 
child can no longer take sweet foods or drinks because they feel sick, vomit or get unpleasant effects 
such as bloating, stomach cramps or diarrhoea. 
 
3. How Vimizim is given 
 
Your doctor or nurse will give Vimizim to you by an infusion into a vein. 
 
The medicine has to be diluted before being given. Your doctor or nurse will give you some medicines 
before your treatment to reduce allergic reactions and you may also be given medicines to help control 
any fever. 
 
Dose  
The dose you receive is based on your body weight.  The recommended dose regimen for adults and 
children is 2 mg/kg body weight given once every week through a drip into a vein (intravenous 
infusion). Each infusion will be given over approximately 4 hours. Treatment with Vimizim may be 
started at as young as an age possible and is intended for long term use. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse.  
 
 
4. Possible side effects 
 



 

23 

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 
reactions”). The most serious side effects were severe allergic reactions (seen uncommonly – may 
affect up to 1 in 100 people) and mild to moderate vomiting (seen very commonly – may affect more 
than 1 in 10 people).  Symptoms of allergic reaction include rash, itching or hives on the skin (seen 
commonly – may affect up to 1 in 10 people).  If you experience any difficulty swallowing, talking, 
severe shortness of breath or wheezing, swelling of the face or lips, dizziness or weak pulse; these 
may represent symptoms of a severe allergic reaction and you should tell your doctor 
immediately. Based on the severity of the side effect, your doctor may slow or temporarily interrupt 
the infusion and/ or give you additional medicines to reduce the effects of a severe allergic reaction 
(e.g. antihistamines and/or corticosteroids) or to reduce fever (antipyretics). 
 
Very common side effects include symptoms of infusion reactions such as headache, nausea, fever, 
chills and stomach ache.  Other very common adverse reactions were diarrhoea, mouth and throat pain, 
dizziness and trouble breathing.  
 
Common side effects observed was muscle pain. 
 
Reporting of side effects  
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Vimizim 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and 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. 
 
Store in the original package in order to protect from light. 
 
Do not use Vimizim if the solution is discoloured or it contains visible particles.  
 
After dilution: 
Once the product has been diluted it 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 2oC – 8oC followed by up to 24 hours at 23oC – 27oC during administration. 
 
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 Vimizim contains 
- The active substance is elosulfase alfa. Each ml of concentrate contains 1 mg elosulfase alfa. 

Each vial of 5 ml contains 5 mg elosulfase alfa.  



 

24 

- The other ingredients are: sodium acetate trihydrate, sodium dihydrogen phosphate 
monohydrate, arginine hydrochloride, sorbitol, polysorbate 20, and water for injections (see 
section 2 under ‘Vimizim contains sodium and sorbitol (E420)’). 

 
What Vimizim looks like and contents of the pack  
Vimizim is supplied as a concentrate for solution for infusion (sterile concentrate). The clear to 
slightly opalescent and colourless to pale yellow concentrate must be free of visible particles.  
 
Pack sizes: 1 vial of 5 ml  
 
Marketing Authorization Holder  
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork, P43 R298 
Ireland  
 
Manufacturer  
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork 
Ireland 
  
This leaflet was last revised in MM/YYYY 
 
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: 
 
Vimizim should not be mixed with other medicinal products in the same infusion, except for those 
mentioned below. 
 
Each vial of Vimizim is intended for single use only. Vimizim has to be diluted with sodium chloride 
9 mg/ml (0.9 %) solution for infusion using aseptic technique. Diluted Vimizim solution is to be 
administered to patients using an infusion set. An infusion set equipped with an in-line 0.2 µm filter 
can be used.  
 
Any unused product or waste material is to be disposed of in accordance with local requirements. 
 
Preparation of the Vimizim infusion (Use aseptic technique) 
 
1. The number of vials to be diluted based on the individual patient's weight must be determined and 

removed from the refrigerator in advance in order to allow them to reach 23C – 27C. Do not heat 
or microwave vials.  The recommended dose regimen is 2 mg/kg body weight administered once 
every week through a drip into a vein (by intravenous infusion). Each infusion will take 
approximately 4 hours. 
 Patient weight (kg) multiplied by 2 (mg/kg) = Patient dose (mg) 
 Patient dose (mg) divided by 1 (mg/ml concentrate of Vimizim) = Total number of ml of 

Vimizim 
 Total amount (ml) Vimizim divided by 5 ml per vial = Total number of vials 

 
2. The calculated total number of vials is rounded up to next whole vial. 
3. An infusion bag containing sodium chloride 9 mg/ml (0.9 %) solution for infusion is obtained 

suitable for intravenous administration. The total volume of the infusion is determined by the 
patient’s body weight.  
 Patients weighing less than 25 kg should receive a total volume of 100 ml.  



 

25 

 Patients weighing 25 kg or more should receive a total volume of 250 ml.  
 
4. 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. Do not 
shake vials. 

 
5. A volume of the sodium chloride 9 mg/ml (0.9 %) solution for infusion is to be withdrawn and 

discarded from a 100 ml or 250 ml infusion bag equal to the total volume of Vimizim to be added. 
 
6. The calculated volume of Vimizim from the appropriate number of vials is slowly withdrawn using 

caution to avoid excessive agitation. 
 
7. The volume of Vimizim is to be slowly added to the sodium chloride 9 mg/ml (0.9 %) solution for 

infusion. 
 

When diluted with 100 ml sodium chloride 9 mg/ml (0.9 %) solution for infusion; the initial 
rate will be 3 ml/hr. The infusion rate will be increased every 15 minutes as follows: first increase 
the rate to 6 ml/hr, then increase the rate every 15 minutes by 6 ml/hr increments until a maximum 
rate of 36 ml/hr is reached.  
 
When diluted with 250 ml sodium chloride 9 mg/ml (0.9 %) solution for infusion; the initial 
rate will be 6 ml/hr. The infusion rate will be increased every 15 minutes as follows: first increase 
the rate to 12 ml/hr, then increase the rate every 15 minutes by 12 ml/hr increments until a 
maximum rate of 72 ml/hr is reached. 

 
Patient 
weight 

(kg) 

Total 
infusion 
volume 

(ml) 

Step 1 
Initial 

infusion 
rate 0-15 
minutes 
(ml/hr) 

Step 2 
15-30 

minutes 
(ml/hr) 

Step 3 
30-45 

minutes 
(ml/hr) 

Step 4 
45-60 

minutes 
(ml/hr) 

Step 5 
60-75 

minutes 
(ml/hr) 

Step 6 
75-90 

minutes 
(ml/hr) 

Step 7 
90+ 

minutes
(ml/hr) 

< 25 100 3 6 12 18 24 30 36
≥ 25 250 6 12 24 36 48 60 72

Infusion rate may be increased as tolerated by patient.  
 
8. The diluted solution is to be mixed gently prior to infusion.  
 
9. The diluted solution is to be visually inspected for particulate matter prior to use. Do not use if the 

solution is discoloured or if there is particulate matter in the solution 
 
10. The diluted solution 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 23C – 27C during administration. 

 
 


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