ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Aldurazyme 100 U/ml concentrate for solution for infusion
2.
1 ml contains 100 U (approximately 0.58 mg) of laronidase.
Each vial of 5 ml contains 500 U of laronidase.
The activity unit (U) is defined as the hydrolysis of one micromole of substrate (4-MUI) per minute.
Laronidase is a recombinant form of human α-L-iduronidase and is produced by recombinant DNA
technology using mammalian Chinese Hamster Ovary (CHO) cell culture.
Excipients
Each vial of 5 ml contains 1.29 mmol 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.
Aldurazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed
diagnosis of Mucopolysaccharidosis I (MPS I; α-L-iduronidase deficiency) to treat the non-
neurological manifestations of the disease (see section 5.1).
Posology
The recommended dosage regimen of Aldurazyme is 100 U/kg body weight administered once every
week as an intravenous infusion. The initial infusion rate of 2 U/kg/h may be incrementally increased
every fifteen minutes, if tolerated, to a maximum of 43 U/kg/h. The total volume of the administration
should be delivered in approximately 3-4 hours. For information on pre-treatment, see section 4.4.
Paediatric population
No dose adjustment is necessary for the paediatric population.
The safety and efficacy of Aldurazyme in patients older than 65 years have not been established and
no dosage regimen can be recommended in these patients.
The safety and efficacy of Aldurazyme in patients with renal or hepatic insufficiency have not been
evaluated and no dosage regimen can be recommended in these patients.
2
Method of administration
Aldurazyme treatment should be supervised by a physician experienced in the management of patients
with MPS I or other inherited metabolic diseases. Administration of Aldurazyme should be carried out
in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would
be readily available.
For instruction on dilution of the medicinal product before administration, see section 6.6.
Severe hypersensitivity (e.g. anaphylactic reaction) to the active substance or to any of the excipients
(see sections 4.4 and 4.8).
Patients treated with Aldurazyme may develop infusion-associated reactions (IARs), defined as any
related adverse event occurring during the infusion or until the end of the infusion day (see section
4.8). Some of these IARs may be severe (see below).
Patients treated with Aldurazyme should be closely monitored and all cases of infusion-associated
reactions, delayed reactions and possible immunological reactions reported. Antibody status should be
regularly monitored and reported.
Severe infusion associated reactions have been reported in patients with pre-existent severe underlying
upper airway involvement and therefore specifically these patients should continue to be closely
monitored and only be infused with Aldurazyme in an appropriate clinical setting where resuscitation
equipment to manage medical emergencies would be readily available.
Patients with an acute underlying illness at the time of Aldurazyme infusion appear to be at greater
risk for IARs. Careful consideration should be given to the patient’s clinical status prior to
administration of Aldurazyme.
Based on the Phase 3 clinical trial, almost all patients are expected to develop IgG antibodies to
laronidase, mostly within 3 months of initiation of treatment.
Patients who have developed antibodies or symptoms of IARs should be treated with caution when
administering Aldurazyme (see sections 4.3 and 4.8).
In clinical studies IARs were usually manageable by slowing the rate of infusion and by (pre-) treating
the patient with antihistamines and/or antipyretics (paracetamol or ibuprofen), thus enabling the
patient to continue treatment.
As there is little experience on resumption of treatment following prolonged interruption, use caution
due to the theoretical increased risk of hypersensitivity reaction after treatment interruption.
With initial administration of Aldurazyme or upon re-administration following interruption of
treatment, it is recommended that patients be administered pretreatment medicines(antihistamines
and/or antipyretics) approximately 60 minutes prior to the start of the infusion, to minimise the
potential occurrence of IARs. If clinically indicated, administration of pretreatment medications with
subsequent infusions of Aldurazyme should be considered.
In case of a mild or moderate IAR, treatment with antihistamines and paracetamol/ibuprofen should be
considered and/or a reduction in the infusion rate to half the infusion 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/ibuprofen should be considered. The infusion can be
restarted with a reduction of the infusion rate to 1/2 – 1/4 the rate of the infusion at which the reaction
occurred.
3
In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pretreatment should be
considered (antihistamines and paracetamol/ibuprofen and/or corticosteroids) and a reduction of the
infusion rate to 1/2 – 1/4 the rate of the infusion at which the previous reaction occurred.
As with any intravenous protein product, severe allergic-type hypersensitivity reactions are possible.
If these reactions occur, immediate discontinuation of Aldurazyme is recommended and appropriate
medical treatment should be initiated. The current medical standards for emergency treatment are to be
observed.
This medicinal product contains sodium and is administered in 0.9% sodium chloride intravenous
solution (see section 6.6). To be taken into consideration by patients on a controlled sodium diet.
No interaction studies have been performed. Based on its metabolism, laronidase is an unlikely
candidate for Cytochrome P450 mediated interactions.
Aldurazyme should not be administered simultaneously with chloroquine or procaine due to a
potential risk of interference with the intracellular uptake of laronidase.
There are inadequate data on the use of Aldurazyme in pregnant women. Animal studies do not
indicate direct or indirect harmful effects on pregnancy, embryonal/foetal development, parturition and
postnatal development (see section 5.3). The potential risk for humans is unknown. Therefore
Aldurazyme should not be used during pregnancy unless clearly necessary.
Laronidase may be excreted in milk. Because there are no data available in neonates exposed to
laronidase via breast milk, it is recommended to stop breast-feeding during Aldurazyme treatment.
No studies on the effects on the ability to drive and use machines have been performed.
The majority of the related adverse events in the clinical trials were classified as infusion-associated
reactions (IARs), experienced by 53% of the patients in the Phase 3 study (treated for up to 4 years)
and 35% of the patients in the under 5 study (up to 1 year of treatment). Some of the IARs were
severe. Over time the number of these reactions decreased. The most frequent adverse drug reactions
(ADRs) were: headache, nausea, abdominal pain, rash, arthralgia, backpain, pain at extremity,
flushing, pyrexia, infusion site reactions, blood pressure increased, oxygen saturation decreased,
tachycardia and chills.
ADRs to Aldurazyme reported during the Phase 3 study and its extension in a total of 45 patients age 5
years and older and treated up to 4 years are listed below using the following categories of frequency:
very common (≥ 1/10); common (≥ 1/100 to <1/10). Due to the small patient population, an ADR
reported in a single patient is classified as common.
4
MedDRA
System Organ Class
MedDRA
Preferred Term
Frequency
Investigations
Body temperature increased, oxygen
saturation decreased
Common
Cardiac disorders
Tachycardia
Common
Nervous system disorders
Headache
Very common
Paraesthesia, dizziness
Common
Respiratory, thoracic and mediastinal
disorders
Respiratory distress, dyspnoea,
cough
Common
Gastrointestinal disorders
Nausea, abdominal pain
Very common
Vomiting, diarrhoea
Common
Skin and subcutaneous tissue disorders
Rash
Very common
Angioneurotic edema, swelling face,
urticaria, pruritus, cold sweat,
alopecia, hyperhidrosis
Common
Musculoskeletal and connective tissue
disorders
Arthropathy, arthralgia, back pain,
pain in extremity
Very common
Musculoskeletal pain
Common
Vascular disorders
Flushing
Very common
Hypotension, pallor, peripheral
coldness
Common
General disorders and administration site
conditions
Pyrexia, infusion site reaction
Very common
Chills, feeling hot, feeling cold,
fatigue, influenza like illness
Common
Immune system disorders
Anaphylactic reaction
Common
Psychiatric disorders
Restlessness
Common
A single patient with pre-existing airway compromise developed a severe reaction three hours from
the start of the infusion (at week 62 of treatment) consisting of urticaria and airway obstruction,
requiring tracheostomy. This patient tested positive for IgE.
Post-marketing experience of infusion associated reactions revealed reporting of pyrexia, chills,
vomiting, tachypnoea, erythema and cyanosis, in which some of these reactions were severe.
Additionally, a few patients who had a prior history of severe MPS I- related upper airway and
pulmonary involvement, experienced severe reactions including bronchospasm, respiratory arrest, and
facial oedema (see section 4.4).
There have been reports of extravasation in patients treated with Aldurazyme.
Paediatric population
ADRs to Aldurazyme reported during a Phase 2 study in a total of 20 patients, under 5 years of age
and mainly of the severe phenotype, treated up to 12 months are listed below. ADRs were all mild to
moderate in severity.
MedDRA
System Organ Class
MedDRA
Preferred term
Frequency
blood pressure increased
Very common
Investigations
oxygen saturation decreased
Very common
Cardiac disorders
tachycardia
Very common
General disorders and administration site
conditions
pyrexia
Very common
chills
Very common
5
In a phase 4 study 33 MPS1 patients received 1 of 4 dose regimens: 100 U/Kg IV every week
(recommended dose), 200 U/Kg IV every week, 200 U/Kg IV every 2 weeks or 300 U/Kg IV every 2
weeks. The recommended dose group had the fewest number of patients who experienced ADRs and
IARs. The type of IARs was similar to those seen in other clinical studies.
Immunogenicity
Almost all patients developed IgG antibodies to laronidase. Most patients seroconverted within 3
months of initiation of treatment; although seroconversion in patients under 5 years old with a more
severe phenotype occurred mostly within 1 month (mean 26 days versus 45 days in patients 5 years
and older). By the end of the Phase 3 study (or at time of early study withdrawal), 13/45 patients had
no detectable antibodies by radioimmunoprecipitation (RIP) assay, including 3 patients that had never
seroconverted. Patients with absent to low antibody levels showed a robust reduction in urinary GAG
level, whereas patients with high antibody titers showed variable reduction in urinary GAG. The
clinical significance of this finding is unknown since there were no consistent relationships between
IgG antibody level and clinical efficacy endpoints.
In addition 60 patients in the Phase 2 and 3 studies were tested for in-vitro neutralising effects. Four
patients (three in the Phase 3 study and one in the Phase 2 study) showed marginal to low level in vitro
inhibition of laronidase enzymatic activity, which did not appear to impact clinical efficacy and/or
urinary GAG reduction.
The presence of antibodies did not appear to be related to the incidence of IARs, although the onset of
IARs typically coincided with the formation of IgG antibodies. The occurrence of IgE antibodies was
not fully explored.
No case of overdose has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Enzymes,
ATC code: A16AB05.
Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes
required for the catabolism of glycosaminoglycans (GAGs). MPS I is a heterogeneous and
multisystemic disorder characterised by the deficiency of α-L-iduronidase, a lysosomal hydrolase
which catalyses the hydrolysis of terminal α-L-iduronic residues of dermatan sulfate and heparan
sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAGs, dermatan
sulfate and heparan sulfate in many cell types and tissues.
The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to
hydrolyse the accumulated substrate and to prevent further accumulation. After intravenous infusion,
laronidase is rapidly removed from the circulation and taken up by cells into lysosomes, most likely
via mannose-6 phosphate receptors.
Purified laronidase is a glycoprotein with a molecular weight of approximately 83 kD. Laronidase is
comprised of 628 amino acids after cleavage of the N-terminus. The molecule contains 6 N-linked
oligosaccharide modifications sites.
Three clinical trials were performed with Aldurazyme to assess its efficacy and safety. One clinical
study focussed mainly on assessing the effect of Aldurazyme on the systemic manifestations of MPS I
such as poor endurance, restrictive lung disease, upper airway obstruction, reduced joint range of
motion, hepatomegaly and visual impairment. One study mainly assessed the safety and
6
pharmacokinetics of Aldurazyme in patients less than 5 years old, but some efficacy measurements
were included as well. The third study was conducted to evaluate the pharmacodynamics and safety of
different dose regimens of Aldurazyme.
To date there are no clinical data that demonstrate any benefit on the neurological manifestations of
the disorder.
The safety and efficacy of Aldurazyme was assessed in a randomised, double-blind, placebo
controlled, Phase 3 Study of 45 patients, ranging in age from 6 to 43 years. Although patients
representing the full range of the disease spectrum were enrolled, the majority of the patients were of
the intermediate phenotype, with only one patient exhibiting the severe phenotype. Patients were
enrolled with a Forced Vital Capacity (FVC) less than 80% of the predicted value and had to be able to
stand for 6 minutes and to walk 5 meters. Patients received either 100 U/kg of Aldurazyme or placebo
every week for a total of 26 weeks. The primary efficacy endpoints were changes in percent of
predicted normal FVC and absolute distance travelled in the six-minute walk test (6MWT). All
patients subsequently enrolled in an open label extension study where they all received 100 U/kg of
Aldurazyme every week for an additional 3.5 years (182 weeks).
Following 26 weeks of therapy, Aldurazyme-treated patients showed improved respiratory function
and walking ability as compared to placebo as indicated below.
Phase 3, 26 weeks of treatment
compared to placebo
p value Confidence interval
(95%)
Percent Predicted
FVC
(percentage point)
mean 5.6 -
median 3.0 0.009 0.9 - 8.6
6MWT
(meters)
mean 38.1 -
median 38.5 0.066 -2.0 - 79.0
The open label extension study showed improvement and/or maintenance of these effects up to 208
weeks in the Aldurazyme/Aldurazyme group and 182 weeks in the Placebo/Aldurazyme group as
indicated in the table below.
Aldurazyme/Aldurazyme Placebo/Aldurazyme
At 208 weeks At 182 weeks
Mean change from pre-treatment baseline
Percent predicted FVC (%)
1
- 1.2 - 3.3
6 MWT (meters) + 39.2 + 19.4
Apnea/Hypopnea Index (AHI) - 4.0 - 4.8
Shoulder flexion Range Of Motion (degrees) + 13.1 + 18.3
CHAQ/HAQ Disability Index
2
- 0.43 - 0.26
1
The decrease in percent predicted FVC is not clinically significant over this timeframe, and absolute
lung volumes continued to increase commensurate with changes in height in growing paediatric
patients.
2
Both groups exceeded the minimal clinically important difference (-0.24)
Of the 26 patients with abnormal liver volumes at pre-treatment baseline, 22 (85%) achieved a normal
liver size by the end of the study. There was a rapid reduction in the excretion of urinary GAG
(µg/mg creatinine) within the first 4 weeks, which was maintained through the remainder of the study.
Urinary GAG levels decreased by 77% and 66% in the Placebo/Aldurazyme and
Aldurazyme/Aldurazyme groups, respectively; at the end of the study one-third of the patients (15 of
45) had reached normal urinary GAG levels.
7
To address the heterogeneity in disease manifestation across patients, using a composite endpoint that
summed up clinically significant changes across five efficacy variables (percent predicted normal
FVC, 6MWT distance, shoulder flexion range of motion, AHI, and visual acuity) the global response
was an improvement in 26 patients (58%), no change in 10 patients (22%), and a deterioration in 9
patients (20%).
A Phase 2 open-label, 1-year study was conducted that mainly assessed the safety and
pharmacokinetics of Aldurazyme in 20 patients less than 5 years of age at the time of enrolment (16
patients with the severe phenotype and 4 with the intermediate phenotype). The patients were
scheduled to receive Aldurazyme 100 U/kg weekly infusions for a total duration of 52 weeks. Four
patients underwent dosage increases to 200 U/kg for the last 26 weeks because of elevated urinary
GAG levels at Week 22.
Eighteen patients completed the study. Aldurazyme was well tolerated at both dosages. The mean
urinary GAG level declined by 50% at Week 13 and was reduced by 61% at the end of the study.
Upon study completion, all patients showed reductions in liver size and 50% (9/18) had normal liver
size. The proportion of patients with mild left ventricular hypertrophy decreased from 53% (10/19) to
17% (3/18), and mean left ventricular mass normalized for body surface area decreased by 0.9 Z-Score
(n=17). Several patients showed an increase in height (n=7) and weight (n=3) for age Z-score. The
younger patients with the severe phenotype (< 2.5 years) and all 4 patients with the intermediate
phenotype exhibited a normal rate of mental development, whereas the older patients with a severe
phenotype made limited or no gains in cognition.
A phase 4 study was conducted to evaluate the pharmacodynamic effects on urinary GAGs, liver
volume, and 6MWT, of different Aldurazyme dose regimens. In this 26-week open label study, 33
MPS1 patients received 1 of 4 dose regimens of Aldurazyme: 100 U/Kg IV every week (recommended
dose), 200 U/Kg IV every week, 200 U/Kg IV every 2 weeks; or 300 U/Kg IV every 2 weeks. No
definite benefit was shown with the higher doses over the recommended dose. The 200 U/Kg IV every
2 weeks regimen may be an acceptable alternative for patients with difficulty receiving weekly
infusions; however, there is no evidence that the long term clinical efficacy of these two dose regimens
is equivalent.
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 (EMEA) will review any new information which may become
available every year and this SPC will be updated as necessary.
5.2 Pharmacokinetic properties
After intravenous administration of laronidase with an infusion time of 240 minutes and at a dose of
100 U/kg body weight pharmacokinetic properties were measured at Weeks 1, 12 and 26.
Parameter
Infusion 1
Infusion 12
Infusion 26
Mean ± SD
Mean ± SD
Mean ± SD
Cmax (U/ml)
0.197 ± 0.052
0.210 ± 0.079
0.302 ± 0.089
AUC
∞
(h•U/ml)
0.930 ± 0.214
0.913 ± 0.445
1.191 ± 0.451
CL (ml/min/kg)
1.96 ± 0.495
2.31 ± 1.13
1.68 ± 0.763
Vz (l/kg)
0.604 ± 0.172
0.307 ± 0.143
0.239 ± 0.128
Vss (l/kg)
0.440 ± 0.125
0.252 ± 0.079
0.217 ± 0.081
t
1/2
(h)
3.61 ± 0.894
2.02 ± 1.26
1.94 ± 1.09
C
max
showed an increase over time. The volume of distribution decreased with continued treatment,
possibly related to antibody formation and/or decreased liver volume.
The pharmacokinetic profile in patients less than 5 years old was similar to that of older and less
severely affected patients.
8
Laronidase 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 laronidase in a
clinically significant way. Renal elimination of laronidase is considered to be a minor pathway for
clearance (see section 4.2).
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, single dose toxicity, repeated dose toxicity and toxicity to reproduction. Genotoxic and
carcinogenic potential are not expected.
6.
6.1 List of excipients
Sodium chloride
Sodium phosphate monobasic, monohydrate
Sodium phosphate dibasic, heptahydrate
Polysorbate 80
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products except those mentioned in 6.6.
6.3 Shelf life
Unopened vials:
3 years
Diluted solutions:
From a microbiological safety point of view, the product should be used immediately. If not used
immediately, in-use storage should not be longer than 24 hours at 2°C - 8°C provided that dilution has
taken place under controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
For storage conditions of the diluted medicinal product, see section 6.3.
6.5
Nature and contents of container
5 ml concentrate for solution in a vial (type I glass) with a stopper (siliconised chlorobutyl rubber) and
a seal (aluminium) with a flip-off cap (polypropylene).
Pack sizes: 1, 10 and 25 vials.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal and other handling
Each vial of Aldurazyme 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
9
recommended that the diluted Aldurazyme solution be administered to patients using an infusion set
equipped with a 0.2 µm in-line filter.
Preparation of the Aldurazyme Infusion (Use Aseptic Technique)
Determine the number of vials to be diluted based on the individual patient's weight. Remove
the required vials from the refrigerator approximately 20 minutes in advance in order to allow
them to reach room temperature (below 30˚C).
Before dilution, visually inspect each vial for particulate matter and discoloration. The clear to
slightly opalescent and colourless to pale yellow solution should be free of visible particles. Do
not use vials exhibiting particles or discoloration.
Determine the total volume of infusion based on the individual patient's weight, either 100 ml
(if body weight is less or equal than 20 kg) or 250 ml (if body weight is more than 20 kg) of
sodium chloride 9 mg/ml (0.9%) solution for infusion.
Withdraw and discard a volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion
from the infusion bag equal to the total volume of Aldurazyme to be added.
Withdraw the required volume from the Aldurazyme vials and combine the withdrawn volumes.
Add the combined volumes of Aldurazyme to the sodium chloride 9 mg/ml (0.9%) solution for
infusion.
Mix the solution for infusion gently.
Prior to use visually inspect the solution for particulate matter. Only clear and colourless
solutions without visible particles should be used.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands.
8.
EU/1/03/253/001-003
9.
Date of first authorisation: 10/06/2003
Date of latest renewal: 10/06/2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/
10
ANNEX II
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
11
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, Galli Drive Facility, 46 Galli Drive, Novato, CA 94949, USA
Name and address of the manufacturer responsible for batch release
Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, 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 Marketing Authorisation Holder 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.
Clinical aspects:
Regarding the MPS I registry already implemented. This Registry will collect long-term safety and
efficacy data in patients treated with Aldurazyme as well as data on the natural progression of the
disease in patients not on treatment. Annual updates will be provided at the time of the annual
reassessments.
12
ANNEX III
LABELLING AND PACKAGE LEAFLET
13
A. LABELLING
14
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (1 VIAL, 10 VIALS, 25 VIALS)
1.
Aldurazyme 100 U/ml concentrate for solution for infusion
laronidase
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml contains 100 U of laronidase.
Each vial of 5 ml contains 500 U of laronidase.
3.
LIST OF EXCIPIENTS
Excipients:
Sodium chloride, Sodium phosphate monobasic monohydrate, Sodium phosphate dibasic
heptahydrate, Polysorbate 80, Water for injections
4.
1 vial of concentrate for solution for infusion.
10 vials of concentrate for solution for infusion.
25 vials of concentrate for solution for infusion.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before 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
For single use only.
8.
EXPIRY DATE
EXP
15
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C).
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused solution should be discarded.
Marketing Authorisation Holder:
Genzyme Europe B.V.
Gooimeer 10
NL-1411 DD Naarden
The Netherlands
EU/1/03/253/001 1 Vial
EU/1/03/253/002 10 Vials
EU/1/03/253/003 25 Vials
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
16
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Aldurazyme 100 U/ml concentrate for solution for infusion
laronidase
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
5 ml
6.
OTHER
Store at 2°C – 8°C
Genzyme Europe B.V. - NL
17
B. PACKAGE LEAFLET
18
PACKAGE LEAFLET: INFORMATION FOR THE USER
Aldurazyme 100 U/ml concentrate for solution for infusion
Laronidase
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or your pharmacist.
-
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 or pharmacist.
In this leaflet
:
1.
What Aldurazyme is and what it is used for
2.
Before you use Aldurazyme
3.
How to use Aldurazyme
4.
Possible side effects
5
How to store Aldurazyme
6.
Further information
1.
WHAT ALDURAZYME IS AND WHAT IT IS USED FOR
Aldurazyme is used to treat patients with MPS I disease (Mucopolysaccharidosis I). It is given to treat
the non-neurological manifestations of the disease.
People with MPS I disease have either a low level or no level of an enzyme called α-L-iduronidase,
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 I.
Aldurazyme is an artificial enzyme called laronidase. This can replace the natural enzyme which is
lacking in MPS I disease.
2.
BEFORE YOU USE ALDURAZYME
Do not use Aldurazyme
If you are allergic (hypersensitive) to any of the ingredients of Aldurazyme or if you have experienced
a severe allergic reaction to laronidase.
Take special care with Aldurazyme
If you are treated with Aldurazyme, 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 4 “Possible Side Effects”). Some of these reactions may be severe. When you experience such a
reaction,
you should immediately contact your doctor
.
If these reactions occur, the Aldurazyme infusion should be stopped immediately and appropriate
treatment will be started by your doctor.
These reactions may be particularly severe if you have a pre-existing MPS I-related upper airway
obstruction.
You may be given additional medication such as antihistamines and paracetamol to help prevent
allergic-type reactions.
19
Using other medicines
Please inform your doctor if you use medicines containing chloroquine or procaine, due to a possible
risk of decreasing the action of Aldurazyme.
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Pregnancy and breast-feeding
There is not enough experience of the use of Aldurazyme in pregnant women. Aldurazyme should not
be used during pregnancy unless clearly necessary. Ask your doctor or pharmacist for advice before
taking any medicine.
It is not known whether Aldurazyme appears in breast milk. It is recommended to stop breast-feeding
during treatment with Aldurazyme. Ask your doctor or pharmacist for advice before taking any
medicine.
Driving and using machines
The effects on the ability to drive and to use machines have not been studied.
Important information about some of the ingredients of Aldurazyme
This medicinal product contains 1.29 mmol sodium per vial. To be taken into consideration by patients
on a controlled sodium diet.
3.
HOW TO USE ALDURAZYME
Instruction for use - dilution and administration
The concentrate for solution for infusion has to be diluted before administration and is for intravenous
use (see information for health care professionals).
Administration of Aldurazyme should be carried out in an appropriate clinical setting where
resuscitation equipment to manage medical emergencies would be readily available.
Dosage
The recommended dosage regimen of Aldurazyme is 100 U/kg body weight given once every week as
an intravenous infusion. The initial infusion rate of 2 U/kg/h may be gradually increased every fifteen
minutes, if tolerated, to a maximum of 43 U/kg/h. The total volume of the administration should be
delivered in approximately 3-4 hours.
If you forget to use Aldurazyme
If you have missed an Aldurazyme infusion, please contact your doctor.
If you use more Aldurazyme than you should
No case of overdose of Aldurazyme has been reported.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Aldurazyme can cause side effects, although not everybody gets them.
Side effects were mainly seen while patients were being given the medicine or shortly after (infusion-
associated reactions). If you experience any reaction like this,
please tell your doctor immediately.
The number of these reactions decreased the longer that patients were on Aldurazyme. The majority of
these reactions were mild or moderate in intensity. However, a few patients who had a prior history of
severe MPS I related upper airway and pulmonary involvement, experienced severe reactions
including bronchospasm, respiratory arrest, and swelling of the face.
20
The following side effects have been reported:
Very common (occurring in more than 1 in 10 patients)
•
headache
•
nausea
•
abdominal pain
•
rash
•
joint disease, joint pain, back pain, pain in arms or legs
•
flushing
•
fever
•
chills
•
increased heart rate
•
increased blood pressure
•
less oxygen in the blood
•
reaction at the infusion site
Common (occurring in more than 1 in 100 patients and less than 1 in 10 patients)
•
increased body temperature
•
tingling
•
dizziness
•
cough
•
difficulty in breathing which may be extreme
•
vomiting
•
diarrhoea
•
swelling of the face or neck
•
hives
•
itching
•
hair loss
•
cold sweat, heavy sweating
•
muscle pain
•
low blood pressure
•
paleness
•
cold hands or feet
•
feeling hot, feeling cold
•
fatigue
•
influenza like illness
•
allergic reaction
•
restlessness
Unknown frequency
•
Bluish color of the skin (due to lower levels of oxygen in the blood)
•
Fast breathing
•
redness of the skin
•
Leakage of the drug into the surrounding tissue at the site of injection, which may cause
swelling or redness
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE ALDURAZYME
Keep out of the reach and sight of children.
Do not use Aldurazyme after the expiry date which is stated on the label after the letters EXP.
21
Unopened vials:
Store in a refrigerator (2°C – 8°C).
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 Aldurazyme contains
-
The active substance is laronidase. One ml of the solution in the vial contains 100 U of
laronidase. Each vial of 5 ml contains 500 U of laronidase.
-
The other ingredients are:
Sodium chloride, Sodium phosphate monobasic monohydrate, Sodium phosphate dibasic
heptahydrate, Polysorbate 80, Water for injections
What Aldurazyme looks like and contents of the pack
Aldurazyme is supplied as a concentrate for solution for infusion. It is a solution that is clear to
slightly opalescent, and colourless to pale yellow.
Pack size
: 1, 10 and 25 vials per carton. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Genzyme Europe B.V., Gooimeer 10, NL-1411 DD, Naarden, The Netherlands.
Manufacturer
Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom.
22
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien/
/Luxemburg /Luxembourg
Genzyme Belgium N.V.,
Tél/Tel: + 32 2 714 17 11
Magyarország
Genzyme Europe B.V. Képviselet,
Tel: +36 1 310 7440
България
Търговско представителство на
Genzyme CEE GmbH
Тел. +359 2 971 1001
Nederland
Genzyme Europe B.V.,
Tel: +31 35 6991200
Česká republika/Slovenská
Republika/Slovenija
Genzyme Czech, s.r.o.,
Tel: +420 227 133 665
Österreich
Genzyme Austria GmbH,
Tel: + 43 1 774 65 38
Danmark/Norge/Sverige/Suomi/Finland/
Ísland
Genzyme A/S, (Danmark/Tanska/Danmörk),
Tlf/Puh./Sími: + 45 32712600
Polska/Eesti/Latvija/Lietuva
Genzyme Polska Sp. z o.o.
(Poola/Polija/Lenkija),
Tel: + 48 22 24 60 900
Deutschland
Genzyme GmbH,
Tel: +49 610236740
Portugal
Genzyme Portugal S.A.,
Tel: +351 21 422 0100
Ελλάδα/Κύπρος
Genzyme Hellas Ltd. (Ελλάδα)
Τηλ: +30 210 99 49 270
România
Genzyme CEE GmbH- Reprezentanţa pentru
România
Tel: +40 21 243 42 28
España
Genzyme, S.A.,
Tel: +34 91 6591670
United Kingdom/Ireland
Genzyme Therapeutics Ltd. (United Kingdom)
Tel: +44 1865 405200
France
Genzyme S.A.S.,
Tél: + 33 (0) 825 825 863
Italia/Malta
Genzyme Srl (Italia/Italja),
Tel: +39 059 349811
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 (EMEA) 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 (EMEA) web
site: http://www.emea.europa.eu/. There are also links to other websites about rare diseases and
treatments.
23
<--------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
Each vial of Aldurazyme 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 Aldurazyme solution be administered to patients using an infusion set
equipped with an 0.2 µm in-line filter.
From a microbiological safety point of view, the product should be used immediately. If not used
immediately, in-use storage should not be longer than 24 hours at 2°C - 8°C provided that dilution has
taken place under controlled and validated aseptic conditions.
Aldurazyme should not be mixed with other medicinal products in the same infusion.
Preparation of the Aldurazyme Infusion (Use Aseptic Technique)
Determine the number of vials to be diluted based on the individual patient's weight. Remove
the required vials from the refrigerator approximately 20 minutes in advance in order to allow
them to reach room temperature (below 30˚C).
Before dilution, visually inspect each vial for particulate matter and discoloration. The clear to
slightly opalescent and colourless to pale yellow solution should be free of visible particles. Do
not use vials exhibiting particles or discoloration.
Determine the total volume of infusion based on the individual patient's weight, either 100 ml
(if bodyweight is less or equal than 20 kg) or 250 ml (if bodyweight is more than 20 kg) of 0.9%
sodium chloride intravenous solution.
Withdraw and discard a volume of sodium chloride 9 mg/ml (0.9%) solution for infusion from
the infusion bag equal to the total volume of Aldurazyme to be added.
Withdraw the required volume from the Aldurazyme vials and combine the withdrawn volumes.
Add the combined volumes of Aldurazyme to the sodium chloride 9 mg/ml (0.9%) solution for
infusion.
Mix the solution for infusion gently.
Prior to use visually inspect the solution for particulate matter. Only clear and colourless
solutions without visible particles should be used.
Any unused product or waste material should be disposed of in accordance with local requirements.
24
Source: European Medicines Agency
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