ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Naglazyme 1 mg/ml concentrate for solution for infusion
2.
Each ml of solution contains 1 mg galsulfase. One vial of 5 ml contains 5 mg galsulfase.
Galsulfase is a recombinant form of human N-acetylgalactosamine 4-sulfatase and is produced by
recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture.
Excipients
Each 5 ml vial contains 0.8 mmol (18.4 mg) of sodium.
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion.
A clear to slightly opalescent, and colourless to pale yellow solution.
4.
Naglazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed
diagnosis of Mucopolysaccharidosis VI (MPS VI; N-acetylgalactosamine 4-sulfatase deficiency;
Maroteaux-Lamy syndrome) (see section 5.1).
A key issue is to treat children aged <5 years suffering from a severe form of the disease, even though
children <5 years were not included in the pivotal phase 3 study. Limited data are available in patients
< 1 year of age (see section 5.1).
As for all lysosomal genetic disorders, it is of primary importance, especially in severe forms, to
initiate treatment as early as possible, before appearance of non-reversible clinical manifestations of
the disease.
Naglazyme treatment should be supervised by a physician experienced in the management of patients
with MPS VI or other inherited metabolic diseases. Administration of Naglazyme should be carried
out in an appropriate clinical setting where resuscitation equipment to manage medical emergencies
would be readily available
.
Posology
The recommended dose regimen for galsulfase is 1 mg/kg body weight administered once every week
as an intravenous infusion over 4 hours.
2
Special populations
Elderly
The safety and efficacy of Naglazyme in patients older than 65 years has not been established, and no
alternative dose regimen can be recommended in these patients.
Renal and hepatic impairment
The safety and efficacy of Naglazyme in patients with renal or hepatic insufficiency have not been
evaluated (see section 5.2) and no alternative dose regimen can be recommended in these patients.
Paediatric population
There is no evidence for special considerations when Naglazyme is administered to the paediatric
population. Currently available data are described in section 5.1.
Method of administration
The initial infusion rate is adjusted so that approximately 2.5% of the total solution is infused during
the first hour, with infusion of the remaining volume (approximately 97.5%) over the next 3 hours.
100 ml infusion bags should be considered for patients who are susceptible to fluid volume overload
and weigh less than 20 kg; in this case the infusion rate (ml/min) should be decreased so that the total
duration remains no less than 4 hours.
For information on pre-treatment see section 4.4 and for further instructions see section 6.6.
Hypersensitivity to the active substance or to any of the excipients.
Management of compromised airways
Caution must be exercised in the management and treatment of patients with compromised airways by
limitation or careful monitoring of antihistamine and other sedative medicinal product use. Institution
of positive–airway pressure during sleep as well as potential tracheostomy in clinically appropriate
situations should also be considered.
Patients who present with an acute febrile or respiratory illness may need to have their Naglazyme
infusions delayed.
Management of infusion-associated reactions
Patients treated with Naglazyme have developed infusion-associated reactions (IARs), defined as any
adverse reactions occurring during the infusion or until the end of the infusion day (see section 4.8).
Based on data obtained during Naglazyme clinical trials, the majority of patients are expected to
develop IgG antibodies to galsulfase within 4-8 weeks of treatment initiation. In the Naglazyme
clinical trials, IARs were usually manageable by interrupting or slowing the rate of infusion and by
(pre-) treating the patient with antihistamines and/or antipyretics (paracetamol), thus enabling the
patient to continue treatment.
As there is little experience on resumption of treatment following prolonged interruption, caution is to
be used due to the theoretical increased risk of hypersensitivity reaction.
3
With administration of Naglazyme it is recommended that patients be administered pre-treatment
medicinal products (antihistamines with or without antipyretics) approximately 30-60 minutes prior to
the start of the infusion, to minimise the potential occurrence of IARs.
In case of a mild or moderate IAR, treatment with antihistamines and paracetamol should be
considered and/or a reduction in the infusion rate to half the rate at which the reaction occurred.
In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved and
treatment with antihistamines and paracetamol should be considered. The infusion can be restarted
with a reduction of the infusion rate to 50% – 25% of the rate at which the reaction occurred.
In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pre-treatment should be
considered (antihistamines and paracetamol and/or corticosteroids) and a reduction of the infusion rate
to 50% – 25% of the rate at which the previous reaction occurred.
As with any intravenous protein medicinal product, severe allergic-type hypersensitivity reactions are
possible. If these reactions occur, immediate discontinuation of Naglazyme is recommended and
appropriate medical treatment should be initiated. The current medical standards for emergency
treatment are to be observed.
This medicinal product contains 0.8 mmol (18.4 mg) sodium per vial and is administered in sodium
chloride 9 mg/ml solution for injection (see section 6.6). To be taken into consideration by patients on
a controlled sodium diet.
No interaction studies have been performed.
Pregnancy
For Naglazyme, no clinical data on exposed pregnancies are available. Animal studies do not indicate
direct or indirect harmful effects with respect to pregnancy or embryo-foetal development (see
section 5.3). Naglazyme should not be used during pregnancy unless clearly necessary.
Breast-feeding
It is not known whether galsulfase is excreted in milk, therefore breast-feeding should be stopped
during Naglazyme treatment
.
Fertility
Reproduction studies have been performed in rats and rabbits at doses up to 3 mg/kg/day and have
revealed no evidence of impaired fertility or harm to the embryo or foetus due to Naglazyme.
No studies on the effects on the ability to drive and use machines have been performed.
All 39 patients treated up to 6 months in the Phase 3 study experienced Adverse Events (AEs),
regardless of whether they were receiving Naglazyme or placebo.
Adverse reactions are listed in Table 1 by System Organ Class. These are AEs that occurred more
frequently in the Naglazyme group than in the placebo group.
The reactions are listed following the MedDRA frequency convention. Very common adverse
reactions are those with a frequency of ≥1/10. Common reactions have a frequency of ≥1/100 to
<1/10. One case of sleep apnoea was experienced during this study.
4
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1: Percentage and number of patients with selected adverse reactions in the placebo-
controlled study
MedDRA
System Organ Class
MedDRA
Preferred
Term
Frequency
Naglazyme
% (pts)
Placebo%
(pts)
Infections and infestations
Pharyngitis
Common
16 (3)
5 (1)
Gastroenteritis Common
11 (2)
0 (0)
Nervous system disorders
Areflexia
Common
11 (2)
0 (0)
Eye disorders
Conjunctivitis Common
21 (4)
0 (0)
Corneal opacity Common
11 (2)
0 (0)
Ear and labyrinth disorders
Ear pain
Very
common
42 (8)
20 (4)
Vascular disorders
Hypertension Common
11 (2)
0 (0)
Respiratory, thoracic, and mediastinal
disorders
Dyspnoea
Very
common
21 (4)
10 (2)
Apnoea
Common
5 (1)
0 (0)
Nasal
congestion
Common
11 (2)
0 (0)
Gastrointestinal disorders
Abdominal pain
Very
common
42 (8)
30 (6)
Umbilical
hernia
Common
11 (2)
0 (0)
Skin and subcutaneous tissue disorders
Face oedema Common
11 (2)
0 (0)
General disorders and administration site
conditions
Pain
Very
common
26 (5)
5 (1)
Chest pain
Common
16 (3)
5 (1)
Rigors
Common
21 (4)
0 (0)
Malaise
Common
11 (2)
0 (0)
Infusion reactions, defined as adverse reactions occurring during Naglazyme infusions, were observed
in 30 (56%) of the 54 patients treated with Naglazyme across all clinical studies. Reactions began as
early as Week 6 and as late as Week 55 of study medicinal product treatment, and occurred during
multiple infusions though not always in consecutive weeks. The most common symptoms of these
infusion reactions included fever, chills/rigors, rash, and urticaria, although hypotension, nausea,
vomiting, dyspnoea, bronchospasm, retrosternal pain, abdominal pain, headache, malaise, respiratory
stress, angioneurotic oedema and joint pain were also reported.
In four patients <1 year of age, the overall safety profile of a higher dose (2 mg/kg/week) did not differ
in a clinically meaningful manner from that of the recommended 1 mg/kg/week dose, and was
consistent with the safety profile of Naglazyme in older children.
5
Immunogenicity
53/54 patients (98%) treated with Naglazyme across studies were positive for IgG antibodies to
galsulfase.
A comprehensive antibody analysis based on data from three clinical studies has been carried out in 48
patients.
Although a larger proportion of subjects with high total antibody titres experienced recurrent infusion
reactions, neither frequency nor severity could be predicted based on the anti-galsulfase antibody titre.
Likewise, antibody development is not predictive of decreased efficacy although subjects with limited
response in endurance parameters or urinary glycosaminoglycans (GAGs) tended to have higher peak
anti-galsulfase titres than those with good response.
Several patients have received their total dose of Naglazyme at approximately twice the recommended
infusion rate without apparent adverse events.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code:
A16AB08
Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes
required for the catabolism of glycosaminoglycans (GAGs). MPS VI is a heterogeneous and
multisystemic disorder characterized by the deficiency of N-acetylgalactoasamine 4-sulfatase, a
lysosomal hydrolase which catalyses the hydrolysis of sulfate moiety of the glycosaminoglycan,
dermatan sulfate. Reduced or absent N-acetyl galactosamine 4-sulfatase activity results in the
accumulation of dermatan sulfate in many cell types and tissues.
The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to
hydrolyze the accumulated substrate and to prevent further accumulation.
Purified galsulfase, a recombinant form of human N-acetylgalactosamine 4-sulfatase, is a glycoprotein
with a molecular weight of approximately 56 kD. Galsulfase is comprised of 495 amino acids after
cleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modification sites.
After intravenous infusion, galsulfase is rapidly removed from the circulation and taken up by cells
into lysosomes, most likely via mannose-6 phosphate receptors.
The three clinical studies performed with Naglazyme focused on assessing the systemic manifestations
of MPS VI such as endurance, joint mobility, joint pain and stiffness, upper airway obstruction,
manual dexterity and visual acuity.
The safety and efficacy of Naglazyme was assessed in a randomised, double blind, placebo controlled,
Phase 3 study of 39 MPS VI patients, ranging in age from 5 to 29 years. The majority of the patients
presented with short stature, impaired endurance, and musculoskeletal symptoms. Patients who could
walk more than 5 meters (m) but less than 250 m in 6 minutes of a 12 Minute Walk test or less than
400 m at the 12 minute time point at baseline were enrolled in the study.
Patients received either 1 mg/kg of galsulfase or placebo every week for a total of 24 weeks. The
primary efficacy endpoint was the numbers of meters walked in 12 minutes at Week 24 compared to
the number of meters walked at baseline. The secondary efficacy endpoints were the rate of stairs
climbed in three minutes and the urinary glycosaminoglycan excretion of treated patients compared to
6
placebo at Week 24. Thirty-eight patients subsequently enrolled in an Open Label extension study
where they received 1 mg/kg of galsulfase every week.
Following 24 weeks of therapy, Naglazyme-treated patients experienced a 92 ± 40 m improvement in
the distance walked in 12 minutes relative to placebo-treated patients (p = 0.025). Treated patients
experienced a 5.7 stair per minute improvement in the 3 Minute Stair Climb relative to placebo-treated
patients. Treated patients also experienced a mean decrease in urinary glycosaminoglycan excretion of
238 ± 17.8 μg/mg creatinine ± SE following 24 weeks of treatment relative to placebo-treated patients.
GAG results approached the normal range for age in the Naglazyme treatment group.
In an additional Phase 4, randomised, two-dose level study, four MPS VI patients <1 year of age were
treated at 1 or 2 mg/kg/week for 53 to 153 weeks.
Although limited by the very small number of patients that were enrolled, the conclusions that can be
drawn from this study are the following:
Treatment with Naglazyme showed improvement, or lack of worsening, of facial dysmorphism. It did
not prevent the progression of skeletal dysplasia and development of hernias and did not prevent the
progression of corneal clouding. Growth rate remained normal over this limited follow-up period.
Improved hearing was noted in at least one ear for all four subjects. Urinary GAG levels decreased by
more than 70%, consistent with results in older patients.
This medicinal product has been authorised under "Exceptional Circumstances".
This means that due to the rarity of the disease it has not been possible to obtain complete information
on this medicinal product.
The European Medicines Agency will review any new information which may become available every
year and this SmPC will be updated as necessary.
5.2
Pharmacokinetic properties
The pharmacokinetics of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg/kg
of galsulfase as a 4 hour infusion. After 24 weeks of treatment the mean (± Standard Deviation [SD])
maximum plasma concentration (C
max
) was 2,357 (± 1,560) ng/ml and the mean (± SD) area under the
plasma concentration-time curve (AUC
0-t
) was 5,860 (± 4,184) h × ng/ml. The mean (± SD) volume of
distribution (Vz) was 316 (± 752) ml/kg and the mean (± SD) plasma clearance (CL) was
7.9 (± 14.7) ml/min/kg. The mean (± SD) elimination half-life (t
1/2
) was 22.8 (± 10.7) minutes at
Week 24.
Pharmacokinetic parameters in Phase 1 patients have remained stable over the long term (through at
least 194 weeks).
Galsulfase is a protein and is expected to be metabolically degraded through peptide hydrolysis.
Consequently, impaired liver function is not expected to affect the pharmacokinetics of galsulfase in a
clinically significant way. Renal elimination of galsulfase is considered a minor pathway for clearance
(see section 4.2).
5.3 Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of safety
pharmacology, single-dose toxicity, repeated-dose toxicity or on general reproductive performance or
embryo-foetal development in rats or rabbits. Peri- and post-natal toxicity has not been investigated.
Genotoxic and carcinogenic potential are not expected.
The cause of clinical relevance of the hepatic toxicity (bile duct hyperplasia / periportal inflammation)
seen at clinically relevant doses in the repeated dose monkey toxicity study is not known.
7
6.
6.1 List of excipients
Sodium chloride
Sodium phosphate monobasic, monohydrate
Sodium phosphate dibasic, heptahydrate
Polysorbate 80
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
Unopened vials: 3 years.
Diluted solutions:
Chemical and physical in-use stability has been demonstrated for up to 4 days at room temperature
(23°C - 27°C).
From a microbiological safety point of view, Naglazyme should be used immediately. If not used
immediately, in-use storage times and conditions are the responsibility of the user and should normally
not be longer than 24 hours at 2°C - 8°C followed by up to 24 hours at room temperature (23°C -
27°C) during administration.
6.4
Special precautions for storage
Store in a refrigerator (2°C to 8°C).
Do not freeze.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Vial (type I glass) with a stopper (siliconized chlorobutyl rubber) and a seal (aluminium) with a flip-
off cap (polypropylene).
Pack sizes: 1 and 6 vials.
Not all package sizes may be marketed.
6.6 Special precautions for disposal and other handling
Each vial of Naglazyme is intended for single use only. The concentrate for solution for infusion has
to be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion using aseptic technique. It is
recommended that the diluted Naglazyme solution be administered to patients using an infusion set
equipped with a 0.2 µm in-line filter.
Any unused product or waste material is to be disposed of in accordance with local requirements.
Preparation of the Naglazyme infusion (aseptic technique is to be used)
8
The number of vials to be diluted based on the individual patient's weight must be determined and
removed from the refrigerator approximately 20 minutes in advance in order to allow them to reach
room temperature.
Before dilution, each vial is to be inspected for particulate matter and discolouration. The clear to
slightly opalescent and colourless to pale yellow solution must be free of visible particles.
A volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion is to be withdrawn and
discarded from a 250 ml infusion bag equal to the total volume of Naglazyme to be added. 100 ml
infusion bags should be considered for patients who are susceptible to fluid volume overload and
weigh less than 20 kg; in this case the infusion rate (ml/min) should be decreased so that the total
duration remains no less than 4 hours. When using 100 ml bags, the volume of Naglazyme may be
added directly to the infusion bag.
The volume of Naglazyme is to be slowly added to the sodium chloride 9 mg/ml (0.9%) solution for
infusion.
The solution is to be mixed gently before infusion.
The solution is to be visually inspected for particulate matter prior to use. Only clear and colourless
solutions without visible particles should be used.
7.
BioMarin Europe Limited
164 Shaftesbury Avenue
London, WC2H 8HL
United Kingdom
8.
EU/1/05/324/001
EU/1/05/324/002
9.
Date of first authorisation: 24 January 2006
Date of latest renewal: 24 January 2011
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
9
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
10
A
MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
BioMarin Pharmaceutical Inc.
46 Galli Drive, Novato, CA 94949
United States of America
Name and address of the manufacturer responsible for batch release
Catalent UK Packaging Ltd
Wingates Industrial Park,
Westhoughton, Bolton,
Lancs, BL5 3XX
United Kingdom
B
CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan.
An updated Risk Management Plan should be provided as per the CHMP Guideline on Risk
Management System for medicinal products for human use.
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation , is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 002 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by
the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
11
PSURs
The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP.
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame, the results of which shall form the basis of the annual reassessment of the
benefit/risk profile.
12
Specific Obligations:
Description:
Due Date
Module 5 – Clinical
SO2 001.3
Interim results will
be provided in the
CSP Annual
Reports.
To evaluate the long-term safety and efficacy data from Naglazyme treatment
a Clinical Surveillance Program (CSP) will be conducted.
Substudies will be conducted within the CSP that will:
1. Evaluate the effect of Naglazyme on pregnancy and lactation.
2. Evaluate the safety and efficacy of Naglazyme in 10 children less than
5 years of age will be treated with the 1 mg/kg dose for at least one year.
Information will also be collected on clinical status, adverse events,
assessments of immunogenicity and potential effects on antibody formation
The CSP data will be analysed at yearly intervals and results will be submitted
as annual reports.
Detailed clinical status information will be collected at study entry and on an
annual basis for at least 15 years.
Other measures (urinary GAG, antibodies) are assessed more frequently.
Severe and serious liver toxicities will be assessed through the PSUR but also
through analysis of these events in the CSP database.
Subjects enrolled in the program will have urinary glycosaminoglycan and
samples for total antibodies routinely collected as specified in the Schedule of
Activities. Higher antibody levels (≥
65610 DF) will be compared with the
subject’s urinary GAG values with a view to assess potential impacts on
efficacy. Samples from those subjects who have a consistent increase in
urinary GAG values together with high antibody levels will have their
antibody samples assessed for evidence of neutralizing activities.
Samples for total antibody will be collected at specific intervals. If a physician
suspects an IgE mediated reaction they have been advised in the protocol to
request IgE antibody presence to be conducted by the MAH.
The final study report under this CSP will be submitted by 31 July 2020.
A brief update will
be submitted as part
of the Annual
Reassessments.
SOB 002
Final CSP Study
Report:
31 July
2020
To evaluate the long-term safety and efficacy data from Naglazyme treatment
a Clinical Surveillance Program (CSP) will be conducted.
Substudies will be conducted within the CSP that will:
1. Evaluate the effect of Naglazyme on pregnancy and lactation.
2. Evaluate the safety and efficacy of Naglazyme in 10 children less than
5 years of age will be treated with the 1 mg/kg dose for at least one year.
Information will also be collected on clinical status, adverse events,
assessments of immunogenicity and potential effects on antibody formation
The CSP data will be analysed at yearly intervals and results will be submitted
as annual reports.
Detailed clinical status information will be collected at study entry and on an
annual basis for at least 15 years.
Other measures (urinary GAG, antibodies) are assessed more frequently.
Severe and serious liver toxicities will be assessed through the PSUR but also
through analysis of these events in the CSP database.
Subjects enrolled in the program will have urinary glycosaminoglycan and
samples for total antibodies routinely collected as specified in the Schedule of
Activities. Higher antibody levels (≥
65610 DF) will be compared with the
subject’s urinary GAG values with a view to assess potential impacts on
efficacy. Samples from those subjects who have a consistent increase in
urinary GAG values together with high antibody levels will have their
antibody samples assessed for evidence of neutralizing activities.
Samples for total antibody will be collected at specific intervals. If a physician
13
suspects an IgE mediated reaction they have been advised in the protocol to
request IgE antibody presence to be conducted by the MAH.
The final study report under this CSP will be submitted by 31 July 2020.
Several measures will be implemented to assess the Naglazyme dose. Data
collected in the post-marketing phase will also be examined to determine if a
suitable Naglazyme maintenance dose can be recommended relative to the
efficacy endpoints used in the clinical studies.
Interim results will
be provided in the
annual
re-assessment
reports.
14
SO2 003.2
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Naglazyme 1 mg/ml concentrate for solution for infusion
Galsulfase
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml of solution contains 1 mg galsulfase. One vial of 5 ml contains 5 mg galsulfase.
3.
LIST OF EXCIPIENTS
Sodium chloride
Sodium phosphate monobasic monohydrate
Sodium phosphate dibasic heptahydrate
Polysorbate 80
Water for injections
See leaflet for further information.
4.
1 vial of concentrate for solution for infusion
6 vials of concentrate for solution for infusion
5 mg/5 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
17
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator
Do not freeze
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
For single use only
Any unused solution should be discarded
BioMarin Europe Limited
164 Shaftesbury Avenue
London, WC2H 8HL
United Kingdom
EU/1/05/324/001 1 vial
EU/1/05/324/002 6 vials
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
18
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Clear type 1, 5 ml VIAL
1.
Naglazyme 1 mg/ml concentrate for solution for infusion
Galsulfase
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
5 ml
6.
OTHER
Store in a refrigerator
19
B. PACKAGE LEAFLET
20
PACKAGE LEAFLET: INFORMATION FOR THE USER
Naglazyme 1 mg/ml concentrate for solution for infusion
Galsulfase
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, ask your doctor.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1. What Naglazyme is and what it is used for
2. Before you are given Naglazyme
3. How Naglazyme is given
4. Possible side effects
5.
How to store Naglazyme
6.
Further information
1.
WHAT NAGLAZYME IS AND WHAT IT IS USED FOR
Naglazyme is used to treat patients with MPS VI disease (Mucopolysaccharidosis VI).
People with MPS VI disease have either a low level, or no level, of an enzyme called
N-acetylgalactosamine 4-sulfatase, which breaks down specific substances (glycosaminoglycans) in
the body. As a result, these substances do not get broken down and processed by the body as they
should. They accumulate in many tissues in the body, which causes the symptoms of MPS VI.
Naglazyme contains an artificial enzyme called galsulfase. This can replace the natural enzyme which
is lacking in MPS VI disease.
2.
BEFORE YOU ARE GIVEN NAGLAZYME
Do not use Naglazyme
-
If you are allergic (hypersensitive) to galsulfase or any of the other ingredients of Naglazyme.
Take special care with Naglazyme
-
If you are treated with Naglazyme, you may develop infusion-associated reactions. An infusion
associated reaction is any side effect occurring during the infusion or until the end of the
infusion day (see section 4 “Possible Side Effects”). When you experience such a reaction,
you
should immediately contact your doctor.
-
If you have a fever, or if you are having difficulty breathing, talk with your doctor about
delaying your Naglazyme infusion.
-
You may have an allergic reaction to the infusion with
Naglazyme.
If you have an allergic
reaction your doctor may slow down, or stop, your infusion.
Your doctor may also give you
additional medicines to manage any allergic reactions.
Kidney and liver insufficiency
Naglazyme has not been tested in patients with kidney or liver problems. Talk to your doctor if you
have kidney or liver insufficiency.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
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-
Keep this leaflet. You may need to read it again.
Pregnancy
Naglazyme should not be taken during pregnancy unless clearly necessary. Ask your doctor or
pharmacist for advice before taking any medicine.
Breast-feeding
It is not known whether galsulfase is excreted in milk, therefore breast-feeding should be stopped
during Naglazyme treatment. Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed
Important information about some of the ingredients of Naglazyme
Each 5 ml vial contains 0.8 mmol (18.4 mg) of sodium. To be taken into consideration by patients on a
controlled sodium diet.
3.
HOW NAGLAZYME IS GIVEN
Your doctor or nurse will administer the product to you.
The concentrate for solution for infusion has to be diluted prior to administration by intravenous
infusion.
Dose
The recommended dose regimen is 1 mg/kg body weight administered once every week through a drip
into a vein (by intravenous infusion). Each infusion will take approximately 4 hours. For the first hour
the infusion rate will be slow (approximately 2.5% of the total solution), with the remaining volume
(approximately 97.5%) being taken over the next 3 hours.
If you are given more Naglazyme than you should
Naglazyme is administered under the supervision of a nurse or doctor, he or she will check that the
correct dose has been given and act accordingly if necessary.
If you forget to take Naglazyme
If you have missed a Naglazyme infusion, please contact your doctor.
If you have any further questions on the use of this medicine, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Naglazyme can cause side effects, although not everybody gets them.
The following side effects were reported as being related to Naglazyme:
Very common (affects more than 1 user in 10): Abdominal pain, ear pain, pain, reddened eye,
shortness of breath, chills, chest pain, sore throat, stomach pain, poor reflexes, cloudy eyes, swollen
face, gastroenteritis, high blood pressure, malaise, nasal congestion, bulging belly button, fever,
headache, rash, nausea, vomiting and joint pain.
Common (affects 1 to 10 users in 100): Hives, swelling of the tongue and throat, low blood pressure,
difficulty breathing and apnoea.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
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5.
HOW TO STORE NAGLAZYME
Keep out of the reach and sight of children.
Do not take Naglazyme after the expiry date which is stated on the vial after EXP. The expiry date
refers to the last day of that month.
Unopened vials:
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Diluted solutions:
Chemical and physical in-use stability has been demonstrated for up to 4 days at room temperature
(23°C - 27°C).
From a microbiological safety point of view, the product is to be used immediately. If not used
immediately, in-use storage times and conditions are the responsibility of the user and must normally
not be longer than 24 hours at 2°C - 8°C followed by up to 24 hours at room temperature
(23°C - 27°C) during administration.
Do not take Naglazyme if it contains visible particles.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Naglazyme contains
-
The active substance is galsulfase. One ml of Naglazyme contains 1 mg galsulfase. One vial of
5 ml contains 5 mg galsulfase. Galsulfase is recombinant human N-acetylgalactosamine
4-sulfatase produced by genetically engineered Chinese Hamster Ovary (CHO) cells.
-
The other ingredients are: sodium chloride, sodium phosphate monobasic, monohydrate, sodium
phosphate dibasic, heptahydrate, polysorbate 80, water for injections.
What Naglazyme looks like and contents of the pack
Naglazyme is supplied as a concentrate for solution for infusion. The clear to slightly opalescent and
colourless to pale yellow concentrate must be free of visible particles. The solution must be diluted
further before it can be infused.
Pack sizes:
1 and 6 vials. Not all package sizes may be marketed.
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Marketing Authorization Holder
BioMarin Europe Limited
164 Shaftesbury Avenue
London, WC2H 8HL
United Kingdom
Manufacturer
Catalent UK Packaging Ltd.
Wingates Industrial Park,
Westhoughton, Bolton,
Lancs, BL5 3XX
United Kingdom
For any information about this medicine product, please contact the local representative of the
Marketing Authorisation Holder:
24
România
BioMarin Europe Limited
biomarinro@bmrn.com
This leaflet was last approved in
This medicine has been authorised under “exceptional circumstances”.
This means that because of the rarity of this disease it has been impossible to get complete information
on this medicine.
The European Medicines Agency will review any new information on the medicine every year and this
leaflet will be updated as necessary.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
There are also links to other websites about rare diseases and treatments.
25
Ireland
<------------------------------------------------------------------------------------------------------------------------>
The following information is intended for medical or healthcare professionals only:
Naglazyme should not be mixed with other medicinal products in the same infusion, except for those
mentioned below.
Each vial of Naglazyme is intended for single use only. The concentrate for solution for infusion has
to be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion using aseptic technique. It is
recommended that the diluted Naglazyme solution be administered to patients using an infusion set
equipped with a 0.2 µm in-line filter.
Any unused product or waste material is to be disposed of in accordance with local requirements.
Preparation of the Naglazyme Infusion (Use Aseptic Technique)
The number of vials to be diluted based on the individual patient's weight must be determined and
removed from the refrigerator approximately 20 minutes in advance in order to allow them to reach
room temperature.
Before dilution, each vial is to be inspected for particulate matter and discolouration. The clear to
slightly opalescent and colourless to pale yellow solution must be free of visible particles.
A volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion is to be withdrawn and
discarded from a 250 ml infusion bag equal to the total volume of Naglazyme to be added. 100 ml
infusion bags should be considered for patients who are susceptible to fluid volume overload and
weigh less than 20 kg; in this case the infusion rate (ml/min) should be decreased so that the total
duration remains no less than 4 hours. When using 100 ml bags, the volume of Naglazyme may be
added directly to the infusion bag.
The volume of Naglazyme is to be slowly added to the sodium chloride 9 mg/ml (0.9%) solution for
infusion.
The solution is to be mixed gently for infusion.
The solution is to be visually inspected for particulate matter prior to use. Clear and colourless
solutions without visible particles should be used.
26
Source: European Medicines Agency
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