ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Elaprase 2 mg/ml concentrate for solution for infusion.
2.
Each vial of 3 ml contains 6 mg of idursulfase. Each ml contains 2 mg of idursulfase.
Idursulfase is produced by recombinant DNA technology in a continuous human cell line.
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion.
A clear to slightly opalescent, colourless solution.
4.
Elaprase is indicated for the long-term treatment of patients with Hunter syndrome
(Mucopolysaccharidosis II, MPS II).
Heterozygous females were not studied in the clinical trials.
Elaprase treatment should be supervised by a physician or other healthcare professional experienced in
the management of patients with MPS II disease or other inherited metabolic disorders.
Infusion of Elaprase at home may be considered for patients who have received several months of
treatment in the clinic and who are tolerating their infusions well. Home infusions should be
performed under the surveillance of a physician or other healthcare professional.
Elaprase is administered at a dose of 0.5 mg/kg body weight every week by intravenous infusion over
a 3 hour period, which may be gradually reduced to 1 hour if no infusion-associated reactions are
observed (see section 4.4).
For preparation and administration instructions see section 6.6.
Patients with renal or hepatic impairment
There is no clinical experience in patients with renal or hepatic insufficiency. See section 5.2.
Elderly patients
There is no clinical experience in patients over 65 years of age.
Paediatric patients
The dose for children and adolescents is 0.5 mg/kg body weight weekly.
For preparation and administration instructions see section 6.6.
There is no clinical experience in children under the age of 5.
2
Hypersensitivity to the active substance or to any of the excipients.
Patients treated with idursulfase may develop infusion-related reactions (see section 4.8). During
clinical trials, the most common infusion-related reactions included cutaneous reactions (rash, pruritus,
urticaria), pyrexia, headache, hypertension, and flushing. Infusion-related reactions were treated or
ameliorated by slowing the infusion rate, interrupting the infusion, or by administration of medicines,
such as antihistamines, antipyretics, low-dose corticosteroids (prednisone and methylprednisolone), or
beta-agonist nebulization. No patient discontinued treatment due to an infusion reaction during
clinical studies.
Special care should be taken when administering an infusion in patients with severe underlying airway
disease. These patients should be closely monitored and infused in an appropriate clinical setting.
Caution must be exercised in the management and treatment of such patients by limitation or careful
monitoring of antihistamine and other sedative medicinal product use. Institution of positive-airway
pressure may be necessary in some cases.
Consider delaying the infusion in patients who present with an acute febrile respiratory illness.
Patients using supplemental oxygen should have this treatment readily available during infusion in the
event of an infusion-related reaction.
Patients who develop IgM or IgG antibodies are at a higher risk of infusion reactions and other
adverse reactions, however, IgE antibodies have not been observed.
Anaphylactoid reactions, which have the potential to be life threatening, have been observed in some
patients treated with Elaprase, as with any intravenous protein product. Late emergent symptoms and
signs of anaphylactoid reactions have been observed as long as 24 hours after an initial reaction. If an
anaphylactoid reaction occurs the infusion should be immediately suspended and appropriate
treatment and observation initiated. The current medical standards for emergency treatment are to be
observed. Patients experiencing severe or refractory anaphylactoid reactions may require prolonged
clinical monitoring. Patients who have experienced anaphylactoid reactions should be treated with
caution when re-administering Elaprase.
No formal drug interaction studies have been conducted with Elaprase.
Based on its metabolism in cellular lysosomes, idursulfase would not be a candidate for cytochrome
P450 mediated interactions.
No effects on male fertility were seen in reproductive studies in male rats.
There are no data from the use of idursulfase in pregnant women. Animal studies do not indicate direct
or indirect harmful effects with respect to reproductive toxicity (see Section 5.3). As a precautionary
measure, it is preferable to avoid the use of Elaprase during pregnancy.
It is not known whether idursulfase is excreted in human breast milk. Available data in animals have
shown excretion of idursulfase in milk (see Section 5.3). A risk to the suckling child cannot be
excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue
therapy with Elaprase should be made taking into account the benefit of breast-feeding to the child and
the benefit of Elaprase therapy to the woman.
3
No studies on the effects on the ability to drive and use machines have been performed.
Adverse drug reactions that were reported for the 32 patients treated with 0.5 mg/kg Elaprase weekly
in the Phase II/III 52-week placebo-controlled study were almost all mild to moderate in severity. The
most common were infusion-related reactions, 202 of which were reported in 22 out of 32 patients
following administration of a total of 1580 infusions. In the placebo treatment group 128 infusion-
related reactions were reported in 21 out of 32 patients following administration of a total of 1612
infusions. Since more than one infusion-related reaction may have occurred during any single
infusion, the above numbers are likely to over estimate the true incidence of infusion reactions.
Related reactions in the placebo group were similar in nature and severity to those in the treated group.
The most common of these infusion-related reactions included cutaneous reactions (rash, pruritus,
urticaria), pyrexia, headache, and hypertension. The frequency of infusion-related reactions decreased
over time with continued treatment.
Adverse drug reactions are listed in the table below with information presented by system organ class
and frequency. Frequency is given as very common (>1/10) or common (>1/100, <1/10). The
occurrence of an event in a single patient is defined as common in view of the number of patients
treated. Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness. Adverse drug reactions only reported during the post marketing period are also included
in the table with a frequency of “not known”.
Adverse drug reactions were defined as treatment-emergent events with suspected causality and
excluded non-serious events that were reported only once in a single patient; treatment emergent
events with an excess incidence of at least 9% compared with placebo were also considered as adverse
drug reactions.
System Organ Class
Adverse Drug Reaction (Preferred Term)
Very Common
(≥ 1/10)
Common
(≥ 1/100), < 1/10)
Not Known
Immune system disorders
Anaphylactoid reaction
Nervous system disorders
Headache
Dizziness, tremor
Cardiac disorders
Cyanosis, arrhythmia,
tachycardia
Vascular disorders
Hypertension, flushing Hypotension
Respiratory, thoracic and mediastinal disorders
Wheezing, dyspnoea
Hypoxia, tachypnoea,
bronchospasm, cough
Gastrointestinal disorders
Abdominal pain,
nausea, dyspepsia,
diarrhoea
Swollen tongue
Skin and subcutaneous tissue disorders
Urticaria, rash, pruritus Erythema
Musculoskeletal and connective disorders
Chest pain
Arthralgia
General disorders and administration site conditions
Infusion-related
Face oedema, oedema
4
reaction, pyrexia,
infusion site swelling.
peripheral
Across studies, serious adverse reactions were reported in a total of 5 patients who received 0.5 mg/kg
weekly or every other week. Four patients experienced a hypoxic episode during one or several
infusions, which necessitated oxygen therapy in 3 patients with severe underlying obstructive airway
disease (2 with a pre-existing tracheostomy). The most severe episode occurred in a patient with a
febrile respiratory illness and was associated with hypoxia during the infusion, resulting in a short
seizure. In the fourth patient, who had less severe underlying disease, spontaneous resolution occurred
shortly after the infusion was interrupted. These events did not recur with subsequent infusions using
a slower infusion rate and administration of pre-infusion medicinal products, usually low-dose
steroids, antihistamine, and beta-agonist nebulization. The fifth patient, who had pre-existing
cardiopathy, was diagnosed with ventricular premature complexes and pulmonary embolism during
the study.
There have been post-marketing reports of anaphylactoid reactions. Please see section 4.4 for further
information.
Across all studies, 53/107 patients (50%) developed anti-idursulfase IgG antibodies at some point.
Nine of the IgG positive patients also tested positive for IgM antibodies, and four patients tested
positive for IgA antibodies. In addition, one patient who was not IgG positive developed transient
IgM antibodies and persistent IgA antibodies. The overall neutralizing antibody rate was 26/107
patients (24%). In the 52-week study, rates of seropositivity peaked by Weeks 18 to 27 and steadily
declined thereafter for the remainder of this study.
In general, patients who tested positive for IgG antibodies were more likely to have infusion-related
events than those who did not test positive. However, overall rates of infusion-related adverse events
declined over time, regardless of antibody status. The reduction of urinary GAG excretion was
somewhat less in patients for whom circulating anti-idursulfase antibodies were detected.
There is no experience with overdoses of Elaprase.
5.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Alimentary tract and metabolism products – enzymes, ATC code:
A16AB09
.
Hunter syndrome is an X-linked disease caused by insufficient levels of the lysosomal enzyme
iduronate-2-sulfatase. Iduronate-2-sulfatase functions to catabolize the glycosaminoglycans (GAG)
dermatan sulfate and heparan sulfate by cleavage of oligosaccharide-linked sulfate moieties. Due to
the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome,
glycosaminoglycans progressively accumulate in the cells, leading to cellular engorgement,
organomegaly, tissue destruction, and organ system dysfunction.
Idursulfase is a purified form of the lysosomal enzyme iduronate-2-sulfatase, produced in a human cell
line providing a human glycosylation profile, which is analogous to the naturally occurring enzyme.
Idursulfase is secreted as a 525 amino acid glycoprotein and contains 8 N-linked glycosylation sites
that are occupied by complex, hybrid, and high-mannose type oligosaccharide chains. Idursulfase has
a molecular weight of approximately 76 kD.
5
Treatment of Hunter syndrome patients with intravenous Elaprase provides exogenous enzyme for
uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains
allow specific binding of the enzyme to the M6P receptors on the cell surface, leading to cellular
internalization of the enzyme, targeting to intracellular lysosomes and subsequent catabolism of
accumulated GAG.
A total of 108 male Hunter syndrome patients with a broad spectrum of symptoms were enrolled in
two randomized, placebo-controlled clinical studies, 106 continued treatment in two open-label,
extension studies.
In a 52-week, randomized, double-blind, placebo-controlled clinical study, 96 patients between the
ages of 5 and 31 years received Elaprase 0.5 mg/kg every week (n=32) or 0.5 mg/kg every other week
(n=32), or placebo (n=32). The study included patients with a documented deficiency in iduronate-2-
sulfatase enzyme activity, a percent predicted FVC <80%, and a broad spectrum of disease severity.
The primary efficacy endpoint was a two-component composite score based on the sum of the ranks of
the change from baseline to the end of the study in the distance walked during six minutes (6-minute
walk test or 6MWT) as a measure of endurance, and % predicted forced vital capacity (FVC) as a
measure of pulmonary function. This endpoint differed significantly from placebo for patients treated
weekly (p=0.0049).
Additional clinical benefit analyses were performed on individual components of the primary endpoint
composite score, absolute changes in FVC, changes in urine GAG levels, liver and spleen volumes,
measurement of forced expiratory volume in 1 second (FEV
1
), and changes in left ventricular mass
(LVM).
52 Weeks of Treatment
0.5 mg/kg Weekly
Marginally Weighted (OM)
Mean (SE)
Mean Treatment
Difference
Compared with
Placebo (SE)
P-value
(Compared with
Placebo)
Idursulfase
Placebo
Endpoint
Composite (6MWT
and %FVC)
74.5 (4.5)
55.5 (4.5)
19.0 (6.5)
0.0049
6MWT (m)
43.3 (9.6)
8.2 (9.6)
35.1 (13.7)
0.0131
% Predicted FVC
4.2 (1.6)
-0.04 (1.6)
4.3 (2.3)
0.0650
FVC Absolute
Volume (L)
0.23 (0.04)
0.05 (0.04)
0.19 (0.06)
0.0011
Urine GAG Levels
(μg GAG/mg
creatinine)
-223.3 (20.7)
52.23 (20.7)
-275.5 (30.1)
<0.0001
% Change in Liver
Volume
-25.7 (1.5)
-0.5 (1.6)
-25.2 (2.2)
<0.0001
% Change in Spleen
Volume
-25.5 (3.3)
7.7 (3.4)
-33.2 (4.8)
<0.0001
A total of 11 of 31 (36%) patients in the weekly treatment group
versus
5 of 31 (16%) patients in the
placebo group had an increase in FEV
1
of at least 0.02L at or before the end of the study, indicating a
dose-related improvement in airway obstruction. The patients in the weekly treatment group
experienced a clinically significant 15% mean improvement in FEV
1
at the end of the study.
6
Urine GAG levels were normalized below the upper limit of normal (defined as 126.6 µg GAG/mg
creatinine) in 50% of the patients receiving weekly treatment.
Of the 25 patients with abnormally large livers at baseline in the weekly treatment group, 80% (20
patients) had reductions in liver volume to within the normal range by the end of the study.
Of the 9 patients in the weekly treatment group with abnormally large spleens at baseline, 3 had spleen
volumes that normalized by the end of the study.
Approximately half of the patients in the weekly treatment group (15 of 32; 47%) had left ventricular
hypertrophy at baseline, defined as LVM index >103 g/m
2
. Of these 6 (40%) had normalised LVM by
the end of the study.
All patients received weekly idursulfase up to 3.2 years in an extension to this study (TKT024EXT).
Among patients who were originally randomised to weekly idursulfase in TKT024, mean maximum
improvement in distance walked during six minutes occurred at Month 20 and mean percent predicted
FVC peaked at Month 16.
Among all patients, statistically significant mean increases from treatment baseline (TKT024 baseline
for TKT024 idursulfase patients and Week 53 baseline for TKT024 placebo patients) were seen in the
distance walked 6MWT at the majority of time points tested, with significant mean and percent
increases ranging from 13.7m to 41.5m and from 6.4% to 11.7% (maximum at Month 20). At most
time points tested, patients who were from the original TKT024 weekly treatment group improved
their walking distance to a greater extent that patients in the other 2 treatment groups.
Among all patients, mean % predicted FVC was significantly increased at Month 16, although by
Month 36, it was similar to the baseline. Patients with the most severe pulmonary impairment at
baseline (as measured by % predicted FVC) tended to show the least improvement.
Statistically significant increases from treatment baseline in absolute FVC volume were seen at most
visits for each of the prior TKT024 treatment groups. Mean changes from 0.07L to 0.31L and percent
ranged from 6.3% to 25.1% (maximum at Month 30). The mean and percent changes from treatment
baseline were greatest in the group of patients from the TKT024 study who had received the weekly
dosing, across all time points.
At their final visit 21/31 patients in the TKT024 Weekly group, 24/32 in the TKT024 EOW group and
18/31 patients in the TKT024 placebo group had final normalised urine GAG levels that were below
the upper limit of normal. Changes in urinary GAG levels were the earliest signs of clinical
improvement with idursulfase treatment and the greatest decreases in urinary GAG were seen within
the first 4 months of treatment in all treatment groups; changes from Month 4 to 36 were small. The
higher the urinary GAG levels at baseline, the greater the magnitude of decreases in urinary GAG with
idursulfase treatment.
The decreases in liver and spleen volumes observed at the end of study TKT024 (week 53) were
maintained during the extension study (TKT024EXT) in all patients regardless of the prior treatment
they had been assigned. Liver volume normalised by Month 24 for 73% (52 out of 71) of patients
with hepatomegaly at baseline. In addition, mean liver volume decreased to a near maximum extent
by Month 8 in all patients previously treated, with a slight increase observed at Month 36. The
decreases in mean liver volume were seen regardless of age, disease severity, antibody status or
neutralising antibody status. Spleen volume normalised by Months 12 and 24 for 9.7% of patients in
the TKT024 Weekly group with splenomegaly.
Mean cardiac LVMI remained stable over 36 months of idursulfase treatment within each TKT024
treatment group.
7
No clinical data exist demonstrating a benefit on the neurological manifestations of the disorder.
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 (EMA) will review any new information which may become
available every year and this SPC will be updated as necessary.
5.2 Pharmacokinetic properties
Idursulfase is taken up by selective receptor-mediated mechanisms involving binding to mannose 6-
phosphate receptors. Upon internalization by cells, it is localized within cellular lysosomes, thereby
limiting distribution of the protein. Degradation of idursulfase is achieved by generally well
understood protein hydrolysis mechanisms to produce small peptides and amino acids, consequently
renal and liver function impairment is not expected to affect the pharmacokinetics of idursulfase.
Pharmacokinetics was evaluated in 10 patients at Week 1 and Week 27 following administration of
0.5 mg/kg weekly as a 3-hour infusion. There were no differences in pharmacokinetic parameters
following 27 weeks of treatment.
Parameter
Week 1 (SD)
Week 27 (SD)
C
max
(μg/ml)
1.5 (0.6)
1.1 (0.3)
AUC (min* μg/ml)
206 (87)
169 (55)
T
1/2
(min)
44 (19)
48 (21)
Cl (ml/min/kg)
3.0 (1.2)
3.40 (1.0)
V
ss
(% BW)
21 (8)
25 (9)
5.3
Preclinical safety data
Nonclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, single dose toxicity, repeated dose toxicity, toxicity to reproduction and development
and to male fertility.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/
foetal development, parturition or postnatal development.
Animal studies have shown excretion of idursulfase in breast milk.
6.
6.1 List of excipients
Polysorbate 20
Sodium chloride
Sodium phosphate dibasic, heptahydrate
Sodium phosphate monobasic, monohydrate
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 section 6.6.
8
6.3 Shelf life
2 years
Chemical and physical in-use stability has been demonstrated for 8 hours at 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
and should not be longer than 24 hours at 2 to 8°C.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
3 ml of concentrate for solution for infusion in a 5 ml vial (type I glass) with a stopper (fluoro-resin
coated butyl rubber), one piece seal and blue flip-off cap.
Pack sizes of 1, 4 and 10 vials.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal and other handling
Each vial of Elaprase is intended for single use only and contains 6 mg of idursulfase in 3 ml of
solution. Elaprase is for intravenous infusion and must be diluted in sodium chloride 9 mg/ml (0.9%)
solution for infusion prior to use.
-
Determine the number of vials to be diluted based on the individual patient’s weight and the
recommended dose of 0.5 mg/kg.
-
Do not use if the solution in the vials is discoloured or if particulate matter is present. Do not
shake.
-
Withdraw the calculated volume of Elaprase from the appropriate number of vials.
-
Dilute the total volume required of Elaprase in 100 ml of 9 mg/ml (0.9%) sodium chloride solution
for infusion. Care must be taken to ensure the sterility of the prepared solutions since Elaprase
does not contain any preservative or bacteriostatic agent; aseptic technique must be observed.
Once diluted, the solution should be mixed gently, but not shaken.
Any unused product or waste material should be disposed of in accordance with local requirements.
Shire Human Genetic Therapies AB, Svärdvägen 11D, 182 33 Danderyd, Sweden
8.
EU/1/06/365/001-003
9.
08.01.2007
9
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.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
C.
11
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Shire (TK3)
205 Alewife Brook Parkway
Cambridge, MA 02138
USA
Shire
300 Patriot Way
Lexington MA 02421
USA
Name and address of the manufacturer(s) responsible for batch release
Shire Human Genetic Therapies AB
Åldermansgatan 13, 227 64 Lund
Sweden
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 03 presented in
Module 1.8.1. of the Marketing Authorisation Application, 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 02, of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application 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
12
*
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 EMA.
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of clinical studies, the
results of which shall form the basis of the annual reassessment of the benefit/risk profile.
Specific Obligation 1 – Hunter Outcome Survey (HOS): available data and updates will be provided
within Annual Reassessments.
Specific Obligation 2 – Immunogenicity Sub-Study: available data and updates will be provided
within Annual Reassessments.
Specific Obligation 3 – Under 5 years Sub-Study: available data and updates will be provided within
Annual Reassessments.
Specific Obligation 4- To submit data regarding immunogenicity after re-exposure to idursulfase
within Annual Reassessments.
Specific Obligation 5 - To evaluate the following long term clinical endpoints primarily through the
HOS. These data will be re-evaluated annually and outcomes reported and discussed within the
Annual Reassessments.
-
Assessment of long term pulmonary morbidity (e.g., incidence of infections, pulmonary function
status) and mortality
-
Assessment of long term cardiovascular morbidity (e.g., incidence of events, and
echocardiography data, where available) and mortality
-
Assessment of long term urinary GAG excretion patterns
-
Assessment of long term antibody levels, isotype and correlation to other therapeutic parameters
13
ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON / 1, 4, 10 VIAL
1.
Elaprase 2 mg/ml concentrate for solution for infusion
Idursulfase
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 6 mg of idursulfase Each ml contains 2 mg of idursulfase
3.
LIST OF EXCIPIENTS
Polysorbate 20
Sodium chloride
Sodium phosphate dibasic, heptahydrate
Sodium phosphate monobasic, monohydrate
Water for Injections
4.
1 vial [4, 10 vials] of 3 ml concentrate for solution for infusion
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use
For single use only
Read the enclosed 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
8.
EXPIRY DATE
EXP: {MMM/YYYY}
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
Any unused product or waste material should be disposed of in accordance with local requirements
16
Shire Human Genetic Therapies AB, Svärdvägen 11D, 182 33 Danderyd, Sweden
EU/1/06/365/001-003
13. MANUFACTURER’S BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Not Applicable. In accordance with the Guidance concerning the Braille requirements for labelling
and the package leaflet; there is no need to put Braille on the packaging of products which are only
intended for administration by healthcare professionals, as is the case for Elaprase.
17
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Elaprase 2 mg/ml sterile concentrate
Idursulfase
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the enclosed package leaflet before use
3.
EXPIRY DATE
EXP: {MMM/YYYY}
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
3 ml
6.
OTHER
Store in a refrigerator
Do not freeze
18
B. PACKAGE LEAFLET
19
PACKAGE LEAFLET: INFORMATION FOR THE USER
Elaprase 2 mg/ml concentrate for solution for infusion
Idursulfase
Read all of this leaflet carefully before you start having this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or 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 get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Elaprase is and what it is used for
2.
Before you use Elaprase
4.
Possible side effects
5
How Elaprase is stored
6.
Further information
1.
WHAT ELAPRASE IS AND WHAT IT IS USED FOR
Elaprase is used as enzyme replacement therapy to treat Hunter syndrome (Mucopolysaccharidosis II)
when the level of the enzyme iduronate-2-sulfatase in the body is lower than normal. If you suffer
from Hunter syndrome, a carbohydrate called glycosaminoglycan which is normally broken down by
your body is not broken down and slowly accumulates in various organs in your body causing these
cells to function abnormally, thereby causing problems for various organs in your body which can lead
to tissue destruction and organ failure. Elaprase works by acting as a replacement for the enzyme that
is at a low level, thereby breaking down this carbohydrate in affected cells.
Enzyme replacement therapy is usually administered as a long-term treatment.
2.
BEFORE YOU USE ELAPRASE
Do not use Elaprase
If you are allergic (hypersensitive) to idursulfase or any of the other ingredients of Elaprase.
Take special care with Elaprase
If you are treated with Elaprase you may experience reactions during or following an infusion (see
section 4 Possible Side Effects). The most common symptoms are itching, rash, hives, fever,
headache, increased blood pressure, and flushing (redness). Most of the time you can still be given
Elaprase even if these symptoms occur. If you experience an allergic side effect following
administration of Elaprase, you should contact your doctor immediately. You may be given additional
medicines such as antihistamines and corticosteroids to treat or help prevent allergic-type reactions.
If severe allergic (anaphylactic-type) reactions occur, your doctor will stop the infusion immediately,
and start giving you suitable treatment. You may need to stay in hospital.
Using other medicines
There is no known interaction of Elaprase with other medicines.
20
3.
How to use Elaprase
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Using Elaprase with food and drink
Due to the way the product is broken down by the body interactions with food and drink are unlikely.
Pregnancy and breast-feeding
Use of Elaprase during pregnancy is not recommended. Elaprase may get into breast milk therefore
you should talk to your doctor or pharmacist before using this medicine if you are breast-feeding.
Driving and using machines
It is not known if Elaprase will affect the ability to drive or use machines.
3.
HOW TO USE ELAPRASE
Elaprase should only be used under the supervision of a doctor or healthcare professional (e.g. nurse)
who is knowledgeable in the treatment of Hunter syndrome or other inherited metabolic disorders.
Elaprase has to be diluted in 9 mg/ml (0.9%) sodium chloride solution for infusion before use. The
usual dose is an infusion of 0.5 mg (half a milligram) for every kg you weigh. After dilution Elaprase
is given through a vein (drip feed). The infusion will normally last for 1 to 3 hours and will be given
every week.
If you use more Elaprase than you should
There is no experience with overdoses of Elaprase.
If you forget to have Elaprase
If you have missed an Elaprase infusion, please contact your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Elaprase can cause side effects, although not everybody gets them. Most side
effects are mild to moderate and associated with the infusion, however some side effects may be
serious. Over time the number of these infusion-associated reactions decreases.
Very common side effects (more than 1 per 10) are:
•
Headache
•
Increased blood pressure, flushing (redness)
•
Shortness of breath, wheezing
•
Abdominal pain, nausea
•
Chest pain
•
Hives, rash, itching
•
Fever
•
Infusion site swelling
•
Infusion related reaction (see Section entitled “Take special care with Elaprase”)
Common side effects (more than 1 per 100 but less than 1 per 10)) are:
•
Dizziness, tremor
•
Rapid heart beat, irregular heart beat, bluish skin
•
Decreased blood pressure
21
•
Difficulty breathing, cough, quickened breathing, low oxygen levels in your blood
•
Diarrhoea, swollen tongue
•
Rednessof the skin
•
Pain in the joints
•
Swelling of the extremities, facial swelling
Unknown frequency side effects
•
Serious allergic reactions
If you have problems breathing
, with or without bluish skin,
tell your doctor immediately
.
If any of the side effects becomes serious, or if your notice any side effects not listed in this leaflet,
please tell your doctor.
5.
HOW ELAPRASE IS STORED
Keep out of reach and sight of children.
Do not use Elaprase after the expiry date which is stated on the label after the letters EXP. The expiry
date refers to the last day of that month.
Store in a refrigerator (2°C – 8°C)
Do not freeze
Do not use Elaprase if you notice that there is discolouration or presence of foreign 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 Elaprase contains
The active substance is idursulfase, which is a form of the human enzyme iduronate-2-sulfatase.
Idursulfase is produced in a human cell line by genetic engineering technology.
Each vial of Elaprase contains 6 mg of idursulfase. Each ml contains 2 mg of idursulfase.
The other ingredients are Polysorbate 20
Sodium chloride
Sodium phosphate dibasic, heptahydrate
Sodium phosphate monobasic, monohydrate
Water for injections
What Elaprase looks like and contents of the pack
Elaprase is a concentrate for solution for infusion. It is supplied in a glass vial as a clear to slightly
opalescent, colourless solution.
Each vial contains 3 ml of concentrate
for solution for infusion.
Elaprase is supplied in pack sizes of 1, 4 and 10 vials per carton
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Shire Human Genetic Therapies AB, Svärdvägen 11D, 182 33 Danderyd, Sweden
Manufacturer
Shire Human Genetic Therapies AB, Åldermansgatan 13, 227 64 Lund, Sweden
22
This leaflet was last approved
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 (EMA) will review any new information on the medicine every
year and this leaflet will be updated as necessary.
More detailed information on this medicine is available on the European Medicines Agency (EMA) web
site:
http://www.ema.europa.eu.
There are also links to other web sites about rare disease and treatments.
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The following information is intended for medical or healthcare professionals only:
Instructions for use, handling and disposal
1.
Calculate the total dose to be administered and number of Elaprase vials needed.
2.
Dilute the total volume of Elaprase concentrate for solution for infusion required in 100 ml of
9 mg/ml sodium chloride solution for infusion (0.9%w/v). Care must be taken to ensure the
sterility of the prepared solutions since Elaprase does not contain any preservative or bacteriostatic
agent; aseptic technique must be observed. Once diluted, the solution should be mixed gently, but
not shaken.
3.
The solution should be inspected visually for particulate matter and discolouration prior to
administration. Do not shake.
4.
It is recommended that administration is started as soon as possible. The chemical and physical
stability of the diluted solution has been demonstrated for 8 hours at 25°C.
5.
Do not infuse Elaprase concomitantly in the same intravenous line with other agents.
6.
For single use only. Any unused product or waste material should be disposed of in accordance
with local requirements.
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Source: European Medicines Agency
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