Mepsevii

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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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 
 
Mepsevii 2 mg/mL concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of concentrate contains 2 mg vestronidase alfa*. Each vial of 5 mL concentrate contains 
10 mg vestronidase alfa. 
 
 
*Vestronidase alfa is a recombinant form of human beta-glucuronidase (rhGUS) and is produced in 
Chinese Hamster Ovary cell culture by recombinant DNA technology. 
 
Excipient(s) with known effect 
 
Each vial contains 17.8 mg sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate).  
Colourless to slightly yellow solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Mepsevii is indicated for the treatment of non-neurological manifestations of Mucopolysaccharidosis 
VII (MPS VII; Sly syndrome).  
 
4.2 Posology and method of administration 
 
Treatment should be supervised by a healthcare professional experienced in the management of 
patients with MPS VII or other inherited metabolic disorders. Administration of vestronidase alfa 
should be carried out by an appropriately trained healthcare professional with the ability to manage 
medical emergencies. 
 
Posology 
 
The recommended dose of vestronidase alfa is 4 mg/kg of body weight administered by intravenous 
infusion every two weeks. 
 
To minimise the risk of hypersensitivity reactions, a non-sedating antihistamine with or without an 
antipyretic medicinal product should be administered 30-60 minutes prior to the start of the infusion 
(see section 4.4). Infusion should be avoided if the patient has an acute febrile or respiratory illness at 
the time. 
 
 
 



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Special populations 
 
Elderly 
The safety and efficacy of vestronidase alfa in patients older than 65 years have not been established. 
No alternative dose regimen is recommended in these patients (see section 5.1).  
 
Renal and hepatic impairment 
The safety and efficacy of vestronidase alfa in patients with renal or hepatic impairment have not been 
evaluated. No alternative dose regimen is recommended in these 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 use only. 
 
For instructions on dilution of the medicinal product before administration, see section 6.6. 
 
The total diluted volume of the solution for infusion should be administered with a rate titration 
regimen over approximately 4 hours. 
 
The rate of infusion should be as follows: in the first hour, 2.5% of the total volume will be infused, 
with the balance infused over the subsequent three hours. Any dead space in the lines should be 
accounted for to ensure 2.5% of the total infusion volume is delivered into the patient’s bloodstream 
during the first hour of infusion. The lowest rate administered to a patient in the clinical development 
program was 0.5 mL/hour during the first 30 minutes of infusion, followed by 1 mL/hour over the next 
30 minutes, equalling 0.75 mL as the lowest total volume infused during the first hour.  
 
Do not flush the line containing vestronidase alfa to avoid a rapid bolus of infused enzyme. Due to the 
low infusion rate, additional sodium chloride 9 mg/mL (0.9%) solution for infusion may be added 
through a separate line (piggyback or Y tube) to maintain sufficient intravenous flow. After the first 
hour, the rate can be increased to infuse the remainder of the solution for infusion over 3 hours as 
tolerated according to the recommended rate guidelines in Table 2. 
 
The infusion rate may be slowed, temporarily interrupted or discontinued in the event of 
hypersensitivity reactions (see section 4.4).  
 
Do not infuse Mepsevii with other medicinal products in the infusion tubing. Compatibility with other 
medicinal products has not been evaluated. 
 
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 
 
The effects of treatment with vestronidase alfa should be periodically evaluated and discontinuation of 
treatment should be considered in cases where clear benefits (including stabilisation of disease 
manifestations) are not observed.  
 
As end organ damage progresses over time, it is more difficult for the treatment to reverse the damage 
or to show improvements. It should be considered by the treating physician that the administration of 
vestronidase alfa does not affect the irreversible complications (e.g. skeletal deformities).  
 



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Vestronidase alfa, at the exposure observed in humans, is not expected to cross the blood-brain-barrier 
and therefore it is not likely to impact the neurological manifestations of the disease. 
 
Hypersensitivity reactions including anaphylaxis 
 
Serious hypersensitivity reactions, including anaphylaxis, have been reported with vestronidase alfa; 
therefore, appropriate medical support should be readily available when vestronidase alfa is 
administered.  
 
Infusion should be avoided if the patient has an acute febrile or respiratory illness at the time.  
 
It is recommended that premedication with non-sedating antihistamines with or without antipyretics be 
administered 30-60 minutes prior to the start of the infusion (see section 4.2).  
 
It is important to administer vestronidase alfa according to the recommended infusion rate schedule 
(see Table 2 in section 6.6).  
 
If severe hypersensitivity reactions occur, immediately stop the infusion of vestronidase alfa and 
initiate appropriate treatment. Management of hypersensitivity reactions should be based on the 
severity of the reaction and include temporary interruption or discontinuation of the infusion and/or 
administration of additional antihistamines, antipyretics, and/or corticosteroids for mild to moderate 
reactions. Consider rapid sodium chloride 9 mg/mL (0.9%) solution for infusion for decreased blood 
pressure and oxygen for hypoxia. Patients should be observed for a minimum of 60 minutes after 
completing the infusion of vestronidase alfa.  
 
Patients should be informed of the signs and symptoms of hypersensitivity reactions and instructed to 
seek immediate medical care should such signs and symptoms occur. The risks and benefits of re-
administering vestronidase alfa should be considered following a severe hypersensitivity reaction. 
 
Spinal/Cervical cord compression 
 
Spinal or cervical cord compression is a known and serious complication of MPS VII. During enzyme 
replacement therapy, spinal cord injury can occur due to improved neck and spine mobility. Patients 
with MPS VII receiving vestronidase alfa should be monitored for signs and symptoms of spinal cord 
compression or neck instability including neck or back pain, weakness of limbs, changes in reflexes or 
urinary and faecal incontinence. Appropriate clinical treatment should be immediately sought. 
 
Sodium restricted diet  
 
This medicinal product contains 17.8 mg sodium per vial and is administered in sodium chloride 
9 mg/mL (0.9%) solution for infusion (see section 6.6). For each vial dosed, including the 
corresponding diluent volume, the sodium intake is 35.5 mg sodium. This amount is equivalent to 
1.8% of the WHO recommended maximum daily intake for sodium (2 g). Mepsevii is considered high 
in sodium. This should be taken into consideration during dilution of the medicinal product for 
patients on a controlled sodium diet or for those patients with congestive heart failure needing to 
restrict sodium and total water intake. 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. Because it is a recombinant human protein and its 
enzyme action is within the lysosome, vestronidase alfa is not expected to interact with other 
medicinal products. 



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4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no data on the use of vetronidase alfa in pregnant women. Animal studies with vestronidase 
alfa do not indicate direct or indirect harmful effects with respect to pregnancy or embryo-foetal 
development (see section 5.3).  
 
As a precautionary measure, it is preferable to avoid the use of vestronidase alfa during pregnancy, 
unless the potential benefit to the mother outweighs the potential theoretical risks to the foetus. 
 
Breast-feeding 
 
There are no data from studies in breast-feeding women. It is not known whether vestronidase alfa is 
excreted in human milk, but systemic exposure via breast-milk is not expected. Due to lack of human 
data, vestronidase alfa should only be administered to a breast-feeding woman if the potential benefit 
of vestronidase alfa to the mother and the benefit of breast-feeding to the infant outweighs the 
potential theoretical risks to the infant. 
 
Fertility 
 
No human data are available on the effect of vestronidase alfa on fertility. Animal studies with 
vestronidase alfa do not indicate any impact on male or female fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Mepsevii has no or negligible influence on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
Summary of safety profile 
 
The assessment of adverse reactions was based on the exposure of 23 patients from 4 clinical trials, 
aged 5 months to 25 years, who received vestronidase alfa at doses up to 4 mg/kg once every two 
weeks for up to 136 weeks. Nineteen patients were younger than 18 years of age.  
 
The most common adverse reactions from 4 clinical trials in 23 patients treated with vestronidase alfa 
were anaphylactoid reaction (13%), urticaria (13%), infusion site swelling (13%), infusion site 
extravasation (8.7%), pruritus (8.7%), diarrhoea (8.7%) and rash (8.7%). Most adverse reactions were 
mild to moderate in severity. There was a single adverse reaction of febrile convulsion observed in one 
patient (4.3%); the patient recovered without sequelae.  
 
Tabulated list of adverse reactions  
 
Table 1 lists the adverse reactions reported from 4 clinical trials in 23 patients treated with Mepsevii.  
Adverse reactions are presented by System Organ Class and frequency. Frequencies are defined as 
very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare 
( ≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000).  
 
 
 
 
 
 
 
 
 



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Table 1 Adverse reactions reported in patients treated with Mepsevii 
MedDRA System Organ Class MedDRA Preferred 

Term 
Frequency 

Immune system disorders Anaphylactoid reaction Very common  
Nervous system disorders Febrile convulsion* Common 
Gastrointestinal disorders Diarrhoea Common  
Skin and subcutaneous tissue disorders Urticaria 

Rash** 
Pruritus 

Very common 
Common  
Common  

General disorders and administration site 
conditions 

Infusion site swelling*** 
Infusion site extravasation 

Very common 
Common  

*Refer to description of selected adverse reactions for details on the febrile convulsion reported in 1 of 23 trial 
patients. 
** Rash includes grouped PTs of rash, rash papular, rash pruritic, rash maculo-papular, papule, and macule 
***One adverse reaction of Peripheral swelling is included within the frequency of Infusion site swelling as the 
event is classified as intravenous catheter issue. 
 
Description of selected adverse reactions  
 
Febrile Convulsion  
 
One patient receiving a vestronidase alfa dose of 4 mg/kg experienced a febrile convulsion during 
treatment at the week 66, within 3 days of diphtheria, tetanus, pertussis vaccination. The infusion was 
stopped, the patient received anticonvulsants, antipyretics and antibiotics, and the febrile convulsion 
resolved. The patient subsequently was re-challenged without recurrence and continued on 
vestronidase alfa treatment. This event was assessed as possibly related to vestronidase alfa due to the 
temporal association with the infusion.  
 
Immunogenicity 
 
Seventeen out of 23 patients (74%) from 4 clinical trials developed anti-recombinant human beta-
glucuronidase (rhGUS) antibodies (ADA), ten of whom further developed neutralizing antibodies 
(NAb) on at least one occasion, but not consistently over time. There is no definitive correlation 
between the antibody titre and neutralizing antibody development. In most patients, a pattern of 
attenuated immunogenicity with chronic exposure was suggested by declining antibody titres over 
time on continuous treatment. The presence of ADA (non-NAb and NAb) does not appear to affect 
reduction in the pharmacodynamic marker, urinary glycosaminoglycans (uGAGs) and development of 
hypersensitivity reactions, including infusion associated reactions.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no experience with overdoses of vestronidase alfa. For the 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: 
A16AB18 



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Mechanism of action 
 
Mucopolysaccharidosis VII is a lysosomal storage disorder characterized by the deficiency of beta-
glucuronidase (GUS) that results in glycosaminoglycans (GAGs) accumulation in cells throughout the 
body leading to multisystem tissue and organ damage.  
 
Vestronidase alfa is a recombinant form of human GUS and is intended to provide exogenous GUS 
enzyme for uptake into cellular lysosomes and subsequent catabolism of accumulated GAGs in 
affected tissues. 
 
Clinical efficacy and safety 
 
The clinical program for vestronidase alfa included 23 treatment naïve patients with MPS VII from 
4 clinical trials, aged 5 months to 25 years, who received vestronidase alfa at doses up to 4 mg/kg once 
every two weeks for up to 132 weeks. Nineteen patients were younger than 18 years of age. 
 
Studies 301 and 202 
In a multi-centre, randomized, placebo-controlled, Blind-Start, single-crossover Phase 3 trial (Study 
UX003-CL301, referred to as Study 301), 12 patients with MPS VII received vestronidase alfa 
4 mg/kg every two weeks for 24 to 48 weeks. The patients were randomized in a blinded manner into 
4 groups: 3 patients received vestronidase alfa immediately for 48 weeks (Group A), 3 patients 
received placebo for 8 weeks then vestronidase alfa for 40 weeks (Group B), 3 patients received 
placebo for 16 weeks then vestronidase alfa for 32 weeks (Group C), and 3 patients received placebo 
for 24 weeks then vestronidase alfa for 24 weeks (Group D). Patients who were enrolled in Study 301 
were eligible to roll over to Study UX003-CL202 (referred to as Study 202), an open-label extension 
trial in which patients received additional doses of vestronidase alfa at 4 mg/kg intravenously every 
other week for up to 144 weeks.  
 
Of the 12 patients enrolled in the UX003-CL301, 4 were male and 8 were female and ranged in ages 
from 8 to 25 years (median 14 years). Nine patients were younger than 18 years of age. MPS VII 
diagnosis was confirmed by GUS enzyme activity assay for 5 patients, by genotyping for 3 patients, 
and via both enzyme assay and genotyping for 4 patients. Patients with MPS VII who received 
Hematopoietic Stem Cell Transplant therapy were excluded in this study. The extremely small 
population of patients with MPS VII globally necessitated the enrolment of all patients able to 
participate in this clinical trial, resulting in a highly variable group. Clinical endpoints were not 
assessable in some patients due to their extent of disease, age or level of cognition (23 out of 
72 assessments [~32%] in 6 domains for 12 patients were non-assessable at baseline).  
 
The primary endpoint was the percent reduction in urinary GAG excretion (Dermatan Sulfate, DS) 
before and after 24 weeks of treatment with vestronidase alfa. The key secondary endpoint was the 
multi-domain clinical responder index (MDRI) score consisting of six domains [six-minute walk test 
(6MWT), forced vital capacity (FVC), shoulder flexion, visual acuity, Bruininks-Oseretsky Test of 
Motor Proficiency (BOT-2) fine motor and gross motor function] after 24 weeks of treatment and 
fatigue total score as measured by the Pediatric Quality of Life Multidimensional Fatigue Scale 
(PedsQL). 
 
Minimal important differences (MIDs) were pre-specified for the six MDRI domains plus fatigue, 
which are: 6MWT (≥23 meters and ≥10% change from baseline), FVC (5% absolute change or 10% 
relative change from baseline in FVC%pred), shoulder flexion (20 degree change of both shoulder 
range of motion), visual acuity (3 lines (corrected, both eyes), BOT-2 fine motor (fine motor precision: 
change of 0.72, and manual dexterity: change of 1.47), BOT-2 gross motor (balance: 0.57, and running 
speed and agility: 0.59), and fatigue (10 points of total score). 
 
Primary Endpoint 
 
After 24 weeks of treatment with vestronidase alfa, a rapid and sustained, highly significant reduction 
in uGAG (DS) excretion was achieved with a LS mean (±SE) percentage change of -64.82% 



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(±2.468%) (p<0.0001). All 12 patients were responders, pre-specified as ≥ 50% reduction in uGAG on 
at least one visit during the first 24 weeks of treatment. In addition, uGAG response (% change from 
study week 0) shows a similar magnitude of reduction in uGAG in all groups after crossover to active 
treatment. 
 
Key Secondary Endpoint: Multi-Domain Clinical Responder Index (MDRI) 
 
For the clinical (secondary) endpoints, beneficial responses were observed although not in all patients. 
After 24 weeks of vestronidase alfa treatment, the overall MDRI results, both pre-specified and 
post-hoc (6 MDRI domains plus fatigue domain) analyses, were positive with an increase of 
+0.5 domains (p=0.0527) and +0.8 domains (p=0.0433) including fatigue, respectively (t-test).  
 
Other Investigations 
Study UX003-CL201 (referred to as Study 201) was a single arm, open-label, dose exploration trial 
that enrolled three MPS VII patients, ranging in age from 5 years to 25 years. After 120 weeks of 
exposure to vestronidase alfa, one patient demonstrated a 21% improvement over baseline in forced 
vital capacity (FVC% predicted) on pulmonary function testing in addition to a 105 meter 
improvement in the 6MWT. Two other patients with baseline hepatosplenomegaly had reduction in 
liver volume (24% and 53%) and spleen volume (28% and 47%) after 36 weeks of treatment.  
 
Study UX003-CL203 (referred to as Study 203) was an open-label, uncontrolled single arm study that 
enrolled eight patients less than 5 years of age who received vestronidase alfa at a dose of 4 mg/kg 
vestronidase alfa every two weeks for 48 weeks of treatment period and additional up to 240 weeks 
during optional continuation period. The study evaluated reduction of urinary GAG excretion, growth 
velocity and hepatosplenomegaly.  
 
uGAG reduction 
 
Treatment with vestronidase alfa resulted in a rapid and sustained, significant (p<0.0001) reduction in 
uGAG DS excretion with an LS mean (SE) percent change of -60% (6.6) at Week 4 which was 
sustained at -61% (6.4) at Week 48. Subjects who entered the Continuation Period up to Week 132 
experienced further reduction in uGAG DS. 
 
Growth 
 
At baseline, all 8 subjects had impaired growth. The mean (SD) standing height z-score improved 
from baseline by +0.196 (0.30) at Week 48. A non-significant trend toward increased growth velocity 
was observed after vestronidase alfa treatment, from a mean (SD) z-score of -2.59 (1.49) at baseline to 
-0.392 (2.10) post-baseline (p=0.27). 
 
Hepatomegaly 
 
All subjects with hepatomegaly assessed by ultrasound examination at Baseline (n=3/8) had decreased 
liver size to within normal range for age and sex prior to study termination. 
 
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. 
 
 
 
 



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5.2 Pharmacokinetic properties 
 
The pharmacokinetics of vestronidase alfa were evaluated in a total of 23 MPS VII patients including 
19 paediatric patients and 4 adults from 3 clinical trials. After repeated dosing of 4 mg/kg every other 
week, the maximal serum concentration (Cmax) was 17.3 ± 9.6 µg/mL (mean ± s.d.; range: 4.7 to 
35.7 µg/mL) and the area under the concentration-time curve from time zero to the last measurable 
concentration (AUC0-t) was 50.9 ± 32.2 µg*h/mL (mean ± s.d.; range: 17.4 to 153 µg*h/mL). The 
pharmacokinetics of vestronidase alfa are time independent with repeat dosing. The limited 
pharmacokinetic data at steady state suggest dose proportional increase in exposure of vestronidase 
alfa over the dose range of 1 - 4 mg/kg every other week. 
 
Distribution 
After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard 
deviation the total volume of distribution (Vss) was 0.26 ± 0.13 L/kg (range: 0.10 to 0.60 L/kg). 
 
Biotransformation 
Vestronidase alfa is a recombinant human enzyme and is therefore eliminated by proteolytic 
degradation into small peptides and amino acids. 
 
Elimination 
After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard 
deviation of the total clearance (CL) was 0.079 ± 0.045 L/h/kg (range: 0.038 to 0.20 L/h/kg); the mean 
± standard deviation of the elimination half-life (t1/2) was 2.6 ± 0.6 hours (range: 0.9 to 3.6 hours).  
 
Excretion 
No excretion studies have been conducted in humans. Vestronidase alfa is not expected to be 
eliminated through renal or faecal excretion.   
 
5.3 Preclinical safety data 
 
Nonclinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, single-dose toxicity in rats, repeated dose toxicity in MPS VII mice and juvenile 
monkeys, fertility and embryo-foetal development in rats or rabbits, and pre- and postnatal 
development in rats. 
 
Genotoxicity studies and carcinogenicity studies have not been performed with vestronidase alfa. 
Based on mechanism of action, rhGUS is not expected to be tumorigenic. 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium dihydrogen phosphate dihydrate  
Sodium chloride 
Histidine  
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 
 
36 months 



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After dilution: Chemical and physical in-use stability of the diluted medicinal product has been 
demonstrated for up to 36 hours under refrigeration at 2°C – 8°C followed by up to 6 hours at room 
temperature up to a maximum of 25°C. 
 
From a microbiological safety point of view, the diluted product should be used immediately. If not 
used immediately, in-use storage times and conditions prior to use are the responsibility of the user, 
but should normally not be longer than 36 hours at 2°C – 8°C followed by up to 6 hours at room 
temperature up to a maximum of 25°C. 
 
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  
 
Colourless glass vial (Ph. Eur. Type I) with a rubber stopper with fluoro-resin coating, and an 
aluminium over seal with a plastic flip-off cap.  
 
Pack size: 1 vial containing 5 mL of concentrate for solution for infusion. 
 
6.6 Special precautions for disposal and other handling 
 
Each vial of Mepsevii is intended for single use only. Mepsevii must be diluted with sodium chloride 
9 mg/mL (0.9%) solution for injection using aseptic technique according to the steps described below. 
The diluted solution for infusion should be administered to patients using a low-protein binding 
infusion bag and set (a non di (2-ethylhexyl) phthalate [DEHP] bag could be used) and the application 
of an infusion set equipped with an in-line, low-protein binding 0.2 μm filter is recommended. 
 

1. Determine the number of vials to be diluted based on the patient’s actual weight and the 
recommended dose of 4 mg/kg, using the following calculations (a-b): 

a. Total dose (mg) = Patient’s weight (kg) x 4 mg/kg (recommended dose) 
b. Total number of vials = Total dose (mg) divided by 10 mg/vial 

2.  Round to the next whole vial and remove the required number of vials (refer to Table 2) from 
the refrigerator to allow them to reach room temperature up to a maximum of 25°C. Do not 
heat, microwave or shake vials.  

a. Volume (mL) of calculated dose = Total dose (mg) divided by the 2 mg/mL 
concentration 

3.  Dilute the calculated dose 1:1 using equal volume of sodium chloride 9 mg/mL (0.9%) solution 
for injection for intravenous infusion. The total infusion volume is based on the total Mepsevii 
dose and volume (refer to Table 2). The above calculated dose diluted 1:1 in sodium chloride 
9 mg/mL (0.9%) solution for injection should be added to a new empty infusion bag. Dilution 
preparation should be done at room temperature. 

4. Prior to withdrawing Mepsevii from the vial, visually inspect for particulate matter and 
discolouration. The Mepsevii concentrate solution for infusion should be colourless to slightly 
yellow. Do not use if the solution is discoloured or if there is particulate matter in the solution. 

5. Slowly withdraw Mepsevii from the appropriate number of vials using caution to avoid 
excessive agitation and any air or frothing. A sufficiently large needle (18 gauge) should be 
used to minimise bubbles in the solution. 

6. Slowly add Mepsevii to the infusion bag using care to avoid agitation, ensuring liquid to liquid 
contact without generating bubbles or turbulence.  



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7. Gently rock the infusion bag to ensure proper distribution of Mepsevii. Do not shake the 
solution. 

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  

 
Table 2. Recommended infusion rate schedule by patient weight for administration of Mepsevii 
at recommended dose of 4 mg/kg 

Patient  
 Weight 
Range 
(kg)  

Total 
Mepsevii  

 Dose Range 
(mg)  

Total  
Mepsevii 
Volume 

(rounded)  
(mL)  

Total 
Number of 
Mepsevii 

Vials 

Total 
Infusion 
Volume 

(infused over 
4 hours) (mL)  

Infusion 
Rate for 1st  

Hour (2.5%) 
(mL/h)  

Infusion Rate 
for Subsequent 

3 Hours 
(97.5%/3)  

(mL/h)  
3.5-5.9 14-23.6 10 2 20 0.5 6.5 
6-8.4 24-33.6 15 3 30 0.75 9.75 

8.5-10.9 34-43.6 20 4 40 1 13 
11-13.4 44-53.6 25 5 50 1.25 16.25 

13.5-15.9 54-63.6 30 6 60 1.5 19.5 
16-18.4 64-73.6 35 7 70 1.75 22.75 

18.5-20.9 74-83.6 40 8 80 2 26 
21-23.4 84-93.6 45 9 90 2.25 29.25 

23.5-25.9 94-103.6 50 10 100 2.5 32.5 
26-28.4 104-113.6 55 11 110 2.75 35.75 

28.5-30.9 114-123.6 60 12 120 3 39 
31-33.4 124-133.6 65 13 130 3.25 42.25 

33.5-35.9 134-143.6 70 14 140 3.5 45.5 
36-38.4 144-153.6 75 15 150 3.75 48.75 

38.5-40.9 154-163.6 80 16 160 4 52 
41-43.4 164-173.6 85 17 170 4.25 55.25 

43.5-45.9 174-183.6 90 18 180 4.5 58.5 
46-48.4 184-193.6 95 19 190 4.75 61.75 

48.5-50.9 194-203.6 100 20 200 5 65 
51-53.4 204-213.6 105 21 210 5.25 68.25 

53.5-55.9 214-223.6 110 22 220 5.5 71.5 
56-58.4 224-233.6 115 23 230 5.75 74.75 

58.5-60.9 234-243.6 120 24 240 6 78 
61-63.4 244-253.6 125 25 250 6.25 81.25 

63.5-65.9 254-263.6 130 26 260 6.5 84.5 
66-68.4 264-273.6 135 27 270 6.75 87.75 

68.5-70.9 274-283.6 140 28 280 7 91 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Ultragenyx Germany GmbH  
Friedrichstr. 191 
10117 Berlin 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1301/001 
 
 
 



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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 23 August 2018 
 
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. 
  



13 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 

 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER 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 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 

 

 



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

 

Name and address of the manufacturer(s) of the biological active substance(s)  

Rentschler Biopharma SE 
Erwin-Rentschler-Strasse 21 
88471 Laupheim 
Germany 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Ultragenyx Netherlands B. V. 
Evert van de Beekstraat 1, Unit 104  
1118 CL Schiphol 
The Netherlands 
 
Millmount Healthcare Ltd. 
Block-7, City North Business Campus 
Stamullen, Co. Meath, 
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 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. 

The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation. 

 

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: 



15 

• 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.  

 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 
FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES  

 

This being a marketing authorisation under exceptional circumstances and pursuant to Article 14(8) 
of Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the 
following measures: 

 

Description Due date 
In order to obtain long-term data on effectiveness and safety of treatment with 
Mepsevii and to characterize the entire mucopolysaccharidosis VII, including 
variability of clinical manifestation, progression and natural history, the MAH is 
requested to submit the results of a study based on adequate source of data deriving 
from a Disease Monitoring Program of patients with mucopolysaccharidosis VII. 
 

Reports to be 
submitted as part 
of the annual re-
assessment  
 

 
  



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



18 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Mepsevii 2 mg/mL concentrate for solution for infusion 
vestronidase alfa  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of sterile concentrate contains 2 mg vestronidase alfa. Each vial of 5 mL concentrate 
contains 10 mg vestronidase alfa (10 mg/ 5 mL). 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium dihydrogen phosphate dihydrate  
Sodium chloride 
Histidine  
Polysorbate 20 
Water for injections 
Contains sodium, see package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
1 vial (5 mL)  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Intravenous use after dilution. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 



19 

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 
 
Ultragenyx Germany GmbH  
Friedrichstr. 191 
10117 Berlin 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1301/001  
 
 
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:  
  



20 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
5 mL VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Mepsevii 2 mg/mL sterile concentrate 
vestronidase alfa 
IV use after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
For single use only. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
10 mg/5 mL 
 
 
6. OTHER 
 
  



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



22 

Package leaflet: Information for the user 
 

Mepsevii 2 mg/mL concentrate for solution for infusion 
vestronidase 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. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- 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 Mepsevii is and what it is used for  
2. What you need to know before you are given Mepsevii  
3. How Mepsevii is given 
4. Possible side effects  
5. How to store Mepsevii  
6. Contents of the pack and other information 
 
 
1. What Mepsevii is and what it is used for 
 
What Mepsevii is 
Mepsevii contains an enzyme called vestronidase alfa. This belongs to a group of medicines called 
enzyme replacement therapies. It is used in adults and children of all ages with MPS VII to treat non-
neurological manifestations of the disease (mucopolysaccharidosis VII, also known as Sly Syndrome).  
 
What is MPS VII 
MPS VII is an illness that runs in families, where the body does not produce enough of an enzyme 
called beta–glucuronidase. 
- This enzyme helps to break down sugars in the body called mucopolysaccharides. 
- Mucopolysaccharides are made in the body and they help build bones, cartilage, skin, and 

tendons. 
- These sugars are re-cycled all the time – new ones are made and old ones are broken down.  
- Without enough beta–glucuronidase, parts of these sugars build up in cells, leading to damage 

in the body. 
 
How Mepsevii works  
This medicine replaces beta-glucuronidase – this helps to break down the sugars that collect in the 
tissues of people with MPS VII.  
- Treatment may improve various signs and symptoms of illness, like walking difficulties and 

tiredness. 
 

Starting treatment early in children may stop the illness getting worse and reduce permanent damage. 
 
2. What you need to know before you are given Mepsevii  
 
You must not be given Mepsevii: 



23 

- If you have ever had a severe allergic reaction to vestronidase alfa or any of the other 
ingredients of this medicine (listed in section 6).  

 
Warnings and precautions  
Talk to your doctor before you are given Mepsevii. 

The effects of treatment with vestronidase alfa should be periodically evaluated and discontinuation of 
treatment should be considered in cases where clear benefits (including stabilisation of disease 
manifestations) are not observed. 

It should be considered that the administration of vestronidase alfa does not affect the irreversible 
complications (e.g. skeletal deformities). 

Look out for side effects 

- You may have side effects while you are being given Mepsevii or for up to a day afterwards. 
These side effects are called infusion reactions because they are caused by the infusion (drip) of 
the medicine. They may include an allergic reaction (see section 4). If you have an infusion 
reaction, tell your doctor straight away. 

- If you have an allergic reaction during your infusion your doctor may slow down, or stop your 
infusion. Your doctor may also give (or have given) you other medicines to manage the allergic 
reaction such as an antihistamine or corticosteroid or an antipyretic, a medicine to reduce fever.  

Other symptoms to look out for 

- If you have neck or back pain, feel numb in your arms or legs, or experience lack of control 
over passing water (urine) or stools, tell your doctor straight away. These problems can be 
signs of the illness and may be caused by pressure on your spinal cord. 

 
Other medicines and Mepsevii 
Tell your doctor if you are using, have recently used or might use any other medicines. 
 
Pregnancy and breast-feeding  
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before using this medicine. 
 
You will not be given Mepsevii if you are pregnant unless treatment is clearly necessary. Discuss with 
your doctor if the benefits of using Mepsevii are greater than the possible risks to your unborn baby. 
This is because there is no experience on the use of Mepsevii during pregnancy. 
 
It is not known whether Mepsevii passes into breast milk, but transfer of the medication to your baby 
is not expected. Discuss with your doctor if the benefits of using Mepsevii are greater than the 
potential risk to your baby while breast-feeding.  
 
Driving and using machines 
Mepsevii is not likely to affect you being able to drive or use machines.  
 
Mepsevii contains sodium 
This medicine contains 17.8 mg sodium (main component of cooking/table salt) in each 5-mL vial, 
and is administered with sodium chloride 9 mg/mL as a diluent. Each vial dosed is therefore 
equivalent to 1.8% of the recommended maximum daily dietary intake of sodium for an adult. Take 
this into account if you are on a controlled sodium diet. 
 
 
3. How Mepsevii is given 
 
Treatment with Mepsevii should be started and monitored by your doctor.  
- Your doctor or nurse will give Mepsevii to you by an infusion (drip) into a vein. 
- The medicine has to be diluted before being given. 



24 

- Your doctor may give (or have given) you some medicines to manage the allergic reaction such 
as an antihistamine or corticosteroid or an antipyretic, a medicine to reduce fever. 

 
Dose 
The dose you will receive is based on how much you weigh.  
- The recommended dose is 4 mg for each kg of body weight. 
- The dose is given every two weeks through a drip into a vein (intra-venous infusion).  
- Each infusion will be given over about 4 hours.  
 
If you are given more Mepsevii than you should 
Mepsevii is given to you and monitored by your doctor. He or she will check that the correct dose has 
been given and take action as needed.  
 
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 within a day after the 
infusion (infusion reactions).  
 
Tell your doctor straight away if you notice any of the following side effects – you may need urgent 
medical treatment: 
 
Very common side effects (may affect more than 1 in 10 people): 
- Severe allergic reaction (anaphylactoid reaction) – Symptoms of severe allergic reaction may 

include shortness of breath, wheezing, difficulty breathing, and swelling of the face and tongue. 
Your doctor may give (or have given) you other medicines to manage the allergic reaction such 
as an antihistamine or corticosteroid or an antipyretic, a medicine to reduce fever. 

- Hives (urticaria) 
- Swelling at the infusion site including leaking into the tissue around the vein (infusion site 

swelling or infusion site extravasation) 
 

Common side effects (may affect up to 1 in 10 people): 
- Itching of the skin (pruritus) 
- Loose stools (diarrhoea) 
- Rash 
- Fever with involuntary contractions of muscles of face or limbs (febrile convulsion) 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. 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 Mepsevii 
 
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 after ‘EXP’. The expiry 
date refers to the last day of that month. 
 
Unopened vials: 
- Store in a refrigerator (2°C to 8°C). 
- Do not freeze. 



25 

- Store in the original package in order to protect from light. 
- Do not use this medicine if you notice particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Mepsevii contains  
- The active substance is vestronidase alfa. Each mL of concentrate contains 2 mg vestronidase 

alfa. Each vial of 5 mL concentrate contains 10 mg vestronidase alfa. 

- The other ingredients are: sodium dihydrogen phosphate dihydrate, sodium chloride, histidine, 
polysorbate 20, and water for injections (for sodium, see section 2 under “Mepsevii contains 
sodium”). 

 
What Mepsevii looks like and contents of the pack 
Mepsevii is supplied as a concentrate for solution for infusion (sterile concentrate). The colourless to 
slightly yellow concentrate must be free of visible particles. It is supplied in a clear glass vial with a 
rubber stopper and an aluminium seal with a plastic cap. 
 
Pack size: 1 vial of 5 mL 
 
Marketing Authorisation Holder  
Ultragenyx Germany GmbH  
Friedrichstr. 191 
10117 Berlin 
Germany 
 
Manufacturer 
Ultragenyx Netherlands B. V. 
Evert van de Beekstraat 1, Unit 104  
1118 CL Schiphol 
The Netherlands 
 
Millmount Healthcare Ltd. 
Block-7, City North Business Campus 
Stamullen, Co. Meath, 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
BE, BG, CZ, DK, DE, EE, IE, EL, ES, HR, IT, CY, LV, LT, LU, HU, MT, NL, AT, PL, PT, RO, 
SI, SK, FI, SE, UK 
Ultragenyx Germany GmbH, DE 
Tel/Tél/Teл./Tlf/Τηλ/Puh/Sími : + 49 30 20179810  
 
FR 
Ultragenyx France SAS, FR 
Tél: + 33 185 653761 ou 0800 91 79 24 (numéro vert)  
 
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. 



26 

The European Medicines Agency will review any new information on this medicine every year and 
this leaflet will be updated as necessary. 
 
Other sources of information 
 
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.  
 
 
------------------------------------------------------------------------------------------------------------------------ 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER 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
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES
	A. LABELLING
	B. PACKAGE LEAFLET