ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Yttriga radiopharmaceutical precursor, solution.
2.
1 ml sterile solution contains 0.1-300 GBq Yttrium (
90
Y) on the reference date and time
(corresponding to 0.005-15 micrograms of Yttrium [
90
Y]) (as Yttrium [
90
Y] chloride).
Each 3ml vial contains 0.1-300 GBq, corresponding to 0.005-15 micrograms of Yttrium (
90
Y), at
reference date and time. The volume is 0.02-3 ml.
Each 10ml vial contains contains 0.1-300 GBq, corresponding to 0.005-15 micrograms of Yttrium
(
90
Y), at reference date and time. The volume is 0.02-5 ml. The theoretical specific activity is 20
GBq/microgram of Yttrium (
90
Y) (see section 6.5).
Yttrium (
90
Y) chloride is produced by decay of its radioactive precursor Strontium (
90
Sr). It decay by
emission of beta radiation of 2.281 MeV (99.98 %) of maximal energy to stable Zirconium (
90
Zr).
Yttrium (
90
Y) has a half-life of 2.67 days (64.1 hours).
For a full list of excipients, see section 6.1.
3.
Radiopharmaceutical precursor, solution.
Clear colourless solution, free of particulate matter.
4.
To be used only for the radiolabelling of carrier molecules, which have been specifically developed
and authorised for radiolabelling with this radionuclide.
Radiopharmaceutical precursor - Not intended for direct use in patients.
Yttriga is only to be used by specialists experienced with
in vitro
radiolabelling
Posology
The quantity of Yttriga required for radiolabelling and the quantity of Yttrium (
90
Y)-labelled medicinal
product that is subsequently administered will depend on the medicinal product radiolabelled and its
intended use. Refer to the Summary of Product Characteristics/package leaflet of the particular
medicinal product to be radiolabelled.
Method of administration
Yttriga is intended for
in vitro
labelling of medicinal products which are subsequently administered by
the approved route.
Further information on the preparation of the product is given in section 12.
2
Do not administer Yttriga directly to the patient.
Yttriga is contraindicated in the following cases:
-
Yttrium (
90
Y)-labelled medicinal products are contraindicated in the following case:
-
For information on contraindications to particular Yttrium (
90
Y)-labelled medicinal products prepared
by radiolabelling with Yttriga refer the Summary of Product Characteristics/package leaflet of the
particular medicinal product to be radiolabelled
.
The contents of the vial of Yttriga is not to be administered directly to the patient but must be used for
the radiolabelling of carrier molecules, such as monoclonal antibodies, peptides or other substrates.
Radiopharmaceuticals should be received, used and administered only by authorised persons in
designated clinical settings and receipt, storage, use, transfer and disposal are subject to the regulations
and appropriate licences of the competent authorities.
Radiopharmaceuticals should be prepared by the user in a manner which satisfies both radiation safety
and pharmaceutical quality requirements.
For information concerning special warnings and special precautions for use of Yttrium (
90
Y)-labelled
medicinal products refer to the Summary of Product Characteristics/package leaflet of the medicinal
product to be radiolabelled.
Particular care should be taken when administering radioactive medicinal products to children and
adolescents (from 2 to 16 years old).
No interaction studies of Yttrium (
90
Y) chloride with other medicinal products have been performed,
because Yttriga is a precursor solution for radiolabelling medicinal products.
For information concerning interactions associated with the use of Yttrium (
90
Y)-labelled medicinal
products refer to the Summary of Product Characteristics/package leaflet of the medicinal product to
be radiolabelled.
Women of childbearing potential
Women of childbearing potential have to use effective contraception during and after treatment.
Pregnancy
Yttrium (
90
Y)-labelled medicinal products are contraindicated in established or suspected pregnancy or
when pregnancy has not been excluded (see section 4.3).
Breast-feeding
Before administering a radioactive medicinal product to a mother who is breast-feeding, consideration
should be given to whether the investigation could be reasonably delayed until the mother has ceased
breast-feeding. If the administration cannot be delayed, a lactating mother should be advised to stop
breast-feeding.
3
Hypersensitivity to Yttrium (
90
Y) chloride or to any of the excipients
Established or suspected pregnancy or when pregnancy has not been excluded (see section 4.6)
Further information concerning the use of a Yttrium (
90
Y)-labelled medicinal products in pregnancy
and breast-feeding is specified in the Summary of Product Characteristics of the medicinal product to
be radiolabelled.
Fertility
Further information concerning the use of a Yttrium (
90
Y)-labelled medicinal concerning fertility is
specified in the Summary of Product Characteristics of the medicinal product to be radiolabelled.
Effects on ability to drive and to use machines following treatment by Yttrium (
90
Y)-labelled
medicinal products will be specified in the Summary of Product Characteristics/package leaflet of the
medicinal product to be radiolabelled.
Possible adverse reactions following the intravenous administration of Yttrium (
90
Y)-labelled a
medicinal product prepared by radiolabelling with Yttriga, will be dependent on the specific medicinal
product being used. Such information will be supplied in the Summary of Product
Characteristics/package leaflet of the medicinal product to be radiolabelled. For each patient, exposure
to ionising radiation must be justifiable on the basis of likely clinical benefit. The activity administered
must be such that the resulting radiation dose is as low as reasonably achievable bearing in mind the
need to obtain the intended therapeutic result.
Exposure to ionising radiation is linked with cancer induction and a potential for development of
hereditary defects.
The radiation dose resulting from therapeutic exposure may result in higher incidence of cancer and
mutations. In all cases, it is necessary to ensure that the risks of the radiation are less than from the
disease itself.
The presence of free Yttrium (
90
Y) chloride in the body after an inadvertent administration of Yttriga
will lead to increased bone marrow toxicity and haematopoetic stern cell damage.
Therefore, in case of an inadvertent administration of Yttriga, the radiotoxicity for the patient must be
reduced by immediate (i. e. within 1 hour) administration of preparations containing chelators like Ca-
DTPA or Ca-EDTA in order to increase the elimination of the radionuclide from the body.
The following preparations must be available in medical institutions, which use Yttriga for labelling of
carrier molecules for therapeutic purposes:
-
Ca-DTPA (Trisodium calcium diethylenetriaminepentaacetate) or
These chelating agents suppress yttrium radiotoxicity by an exchange between the calcium ion and the
yttrium due to their capacity of forming water soluble complexes with the chelating ligands (DTPA,
EDTA). These complexes are rapidly eliminated by the kidneys.
1 g of the chelating agents should be administered by slow intravenous injection over 3 – 4 minutes or
by infusion (1 g in 100 – 250 ml of dextrose, or normal saline).
The chelating efficacy is greatest immediately or within one hour of exposure when the radionuclide is
circulating in or available to tissue fluids and plasma. However, a post-exposure interval > 1 hour does
not preclude the administration and effective action of chelator with reduced efficiency.
Intravenous administration should not be protracted over more than 2 hours.
4
-
Ca-EDTA (Calcium disodium ethylenediaminetetraacetate)
In any case the blood parameters of the patient have to be monitored and the appropriate actions
immediately taken if there is evidence of damage to the blood marrow.
The toxicity of the free Yttrium (
90
Y) due to in-vivo release from the labelled biomolecule in the body
during therapy could be reduced by post-administration of chelating agents.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other therapeutic radiopharmaceuticals, ATC code: V10X
The pharmacodynamic properties of Yttrium (
90
Y)-labelled medicinal products prepared by
radiolabelling with Yttriga, prior to administration, will be dependent on the nature of the medicinal
product to be radiolabelled. Refer to the Summary of Product Characteristics/package leaflet of the
particular medicinal product to be radiolabelled.
5.2 Pharmacokinetic properties
The pharmacokinetic properties of Yttrium (
90
Y)-labelled medicinal products prepared by
radiolabelling with Yttriga, prior to administration, will be dependent on the nature of the medicinal
product to be radiolabelled.
In the rat, following intravenous administration, Yttrium (
90
Y) chloride is rapidly cleared from the
blood. At 1 and 24 hours, blood radioactivity decreases from 11.0 % to 0.14 % of the administered
activity. The two main organs where Yttrium (
90
Y) chloride distributes are the liver and bones. In the
liver, 18 % of the injected activity is taken up 5 min after injection. Liver uptake decreases then to
8.4 % 24 hours after injection. In bone, percentage of injected activity increases from 3.1 % at 5 min
to 18 % at 6 hours and then decreases with time. Faecal and urinary elimination is slow: about 31 % of
the administered activity is eliminated in 15 days.
5.3 Preclinical safety data
The toxicological properties of Yttrium (
90
Y)-labelled medicinal products prepared by radiolabelling
with Yttriga prior to administration, will be dependent on the nature of the medicinal product to be
radiolabelled.
There are no data available on the toxicity of Yttrium (
90
Y) chloride nor on its effects on reproduction
in animals or its mutagenic or carcinogenic potential.
6.
6.1 List of excipients
Hydrochloric acid (0.04 M)
6.2 Incompatibilities
Radiolabelling of medicinal products, such as monoclonal antibodies, peptides or other substrates,
with Yttrium (
90
Y) chloride is very sensitive to the presence of trace metal impurities.
1t is important that all glassware, syringe needles etc, used for the preparation of the radiolabelled
medicinal product are thoroughly cleaned to ensure freedom from such trace metal impurities. Only
syringe needles (for example, non-metallic) with proven resistance to dilute acid should be used to
minimise trace metal impurity levels.
5
6.3 Shelf life
Up to 12 days from the date of manufacture.
6.4 Special precautions for storage
Storage should be in accordance with national regulation on radioactive material.
6.5 Nature and contents of container
Colourless type I glass vial of 3 ml with a V-shapped bottom or a 10 ml with a flat bottom with a
PTFE faced chlorobytylrubber stopper or silicon stopper, closed with an aluminium seal.
Pack size: 1 vial
Not all presentations may be marketed.
6.6 Special precautions for disposal
The vial may contain high pressure due to radiolysis (see section 12).
7.
Eckert & Ziegler Nuclitec GmbH
Gieselweg 1
D-38110 Braunschweig
Germany
8.
EU/1/05/322/001
9.
19/01/2006
11. DOSIMETRY
The radiation dose received by the various organs following intravenous administration of an
Yttrium (
90
Y)-labelled medicinal product is dependent on the specific medicinal product being
radiolabelled. Information on radiation dosimetry of each different medicinal product following
administration of the radiolabelled preparation will be available in the Summary of Product
Characteristics/package leaflet of the particular medicinal product to be radiolabelled.
The dosimetry table below is presented in order to evaluate the contribution of non-conjugated
Yttrium (
90
Y) to the radiation dose following the administration of Yttrium (
90
Y)-labelled medicinal
product or resulting from an accidental intravenous injection of Yttriga.
The dosimetry estimates were based on a rat distribution study and the calculations were effected in
accordance with MIRD/ICRP 60 recommendations. Time-points for measurements were 5 min, 1, 6,
24, 96 and 360 hours.
6
Absorbed dose per unit activity administered (mGy/MBq)
Organ
Adult
(70 kg)
15 years
(50 kg)
10 years
(30 kg)
5 years
(17 kg)
1 year
(10 kg)
Newborn
(5 kg)
Adrenals
7.23 E-01
1.09 E+00 2.53 E+00 3.62 E+00 7.23 E+00 2.17 E+01
Blood
4.20 E-02
6.29 E-02
1.47 E-01
2.10 E-01
4.19 E-01
1.26 E+00
Bone marrow
2.58 E+00 3.88 E+00 9.05 E+00 1.29 E+01 2.58 E+01 7.75 E+01
Brain
8.60 E-03
1.29 E-02
3.01 E-02
4.30 E-02
8.60 E-02
2.58 E-01
Carcass
5.82 E-01
8.72 E-01
2.04 E+00 2.91 E+00 5.82 E+00 1.75 E+01
Colon
2.30 E-02
3.46 E-02
8.06 E-02
1.15 E-01
2.30 E-01
6.91 E-01
Femur
7.76 E+00 1.16 E+01 2.72 E+01 3.88 E+01 7.76 E+01 2.33 E+02
Gastro-intestinal
content
1.22 E-01
1.83 E-01
4.26 E-01
6.09 E-01
1.22 E+00
3.66 E+00
Heart
2.53 E-01
3.79 E-01
8.85 E-01
1.26 E+00 2.53 E+00 7.59 E+00
Ileum
1.16 E-02
1.74 E-02
4.06 E-02
5.81 E-02
1.16 E-01
3.48 E-01
Kidneys
2.35 E+00 3.53 E+00 8.24 E+00 1.18 E+01 2.35 E+01 7.06 E+01
Liver
1.27 E+00 1.91 E+00 4.46 E+00 6.37 E+00 1.27 E+01 3.82 E+01
Lungs
4.23 E-01
6.34 E-01
1.48 E+00 2.11 E+00 4.23 E+00 1.27 E+01
Ovaries
3.33 E-01
4.99 E-01
1.17 E+00 1.66 E+00 3.33 E+00 9.99 E+00
Pancreas
7.90 E-02
1.18 E-01
2.76 E-01
3.95 E-01
7.90 E-01
2.37 E+00
Skeletal muscle
6.12 E-04
9.17 E-04
2.14 E-03
3.06 E-03
6.12 E-03
1.83 E-02
Skin
1.02 E-01
1.53 E-01
3.58 E-01
5.11 E-01
1.02 E+00 3.06 E+00
Spleen
4.90 E-01
7.36 E-01
1.72 E+00 2.45 E+00 4.90 E+00 1.47 E+01
Stomach
6.47 E-02
9.70 E-02
2.26 E-01
3.23 E-01
6.47 E-01
1.94 E+00
Thymus
7.34 E-02
1.10 E-01
2.57 E-01
3.67 E-01
7.34 E-01
2.20 E+00
Thyroids
9.99 E-01
1.50 E+00 3.50 E+00 5.00 E+00 9.99 E+00 3.00 E+01
Urinary bladder 3.62 E-01
5.44 E-01
1.27 E+00 1.81 E+00 3.62 E+00 1.09 E+01
Uterus
1.51 E-02
2.26 E-02
5.28 E-02
7.55 E-02
1.51 E-01
4.53 E-01
Effective Dose
(mSv/MBq)
6.65 E-01
9.98 E-01
2.33 E+00
3.33 E+00
6.65 E+00
1.99 E+1
For this product the effective dose to a 70 kg adult resulting from an intravenously injected activity of
1 GBq is 665 mSv.
12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS
Before use, packaging and radioactivity should be checked. Activity may be measured using an
ionisation chamber. Yttrium (
90
Y) is a beta pure emitter. Activity measurements using an ionisation
chamber are very sensitive to geometric factors and, therefore, should be performed only under
geometric conditions which have been appropriately validated.
Usual precautions regarding sterility and radioactivity should be respected.
The vial should never be opened and must be kept inside its lead shielding. The product should be
aseptically withdrawn through the stopper using sterilised single use needle and syringe after
disinfecting the stopper.
Appropriate aseptic precautions should be taken, complying with the requirements of Good
Pharmaceutical Manufacturing Practice, in order to maintain the sterility of Yttriga and to maintain
sterility throughout the labelling procedures.
The administration of radioactive medicinal products creates risks for other persons from external
radiation or contamination from spills of urine, vomiting, etc. Radiation protection precautions in
accordance with national regulations must therefore be taken.
7
Any unused product or waste material should be disposed of in accordance with local requirements.
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
8
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
9
A
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Eckert & Ziegler Nuclitec GmbH
Gieselweg 1
38110 Braunschweig
Germany
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 aplicable.
10
ANNEX III
LABELLING AND PACKAGE LEAFLET
11
A. LABELLING
12
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
TIN CAN AND LEAD POT
1.
Yttriga radiopharmaceutical precursor, solution.
Yttrium (
90
Y) chloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Yttrium (
90
Y) chloride
Act.: (Y) GBq/vial
Cal.: {DD/MM/YYYY} (12h CET)
Specific activity at calibration: (Y) GBq/vial
3.
LIST OF EXCIPIENTS
Hydrochloric acid (0.04 M)
4.
Radiopharmaceutical precursor, solution.
1 vial
Vol.: {Z} ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For
in vitro
radiolabelling. Read the package leaflet before use.
NOT INTENDED FOR DIRECT ADMINISTRATION TO PATIENTS
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
The vial may contain high pressure due to radiolysis.
8.
EXPIRY DATE
13
EXP {MM/YYYY} (12h CET)
9.
SPECIAL STORAGE CONDITIONS
Store in the original package.
Storage should be in accordance with local regulations for radioactive substances.
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.
Eckert & Ziegler Nuclitec GmbH
Gieselweg 1
D-38110 Braunschweig
Germany
EU/1/05/322/001
13. BATCH NUMBER
BN
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
14
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL ON PERSPEX SHIELD
1.
Yttriga radiopharmaceutical precursor, solution.
Yttrium (
90
Y) chloride
2.
METHOD OF ADMINISTRATION
For
in vitro
radiolabelling.
Read the package leaflet before use.
NOT INTENDED FOR DIRECT APPLICATION TO PATIENTS
3.
EXPIRY DATE
EXP (12h CET)
4.
BATCH NUMBER
BN
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
Vol.: {Z} ml
Act.: {Y}________GBq/vial Cal.: {DD/MM/AAAA} (12h CET)
6.
OTHER
15
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Yttriga solution
Yttrium (
90
Y) chloride
2.
METHOD OF ADMINISTRATION
in vitro labelling
3.
EXPIRY DATE
Exp
4.
BATCH NUMBER
BN
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
Vol.: {Z} ml
Act.: {Y}________GBq/vial Cal.: {DD/MM/AAAA} (12h CET)
6.
OTHER
16
B. PACKAGE LEAFLET
17
PACKAGE LEAFLET: INFORMATION FOR THE USER
Yttriga radiopharmaceutical precursor, solution.
Yttrium (
90
Y) Chloride
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 pharmacist .
-
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 Yttriga is and what it is used for
2.
Before you use Yttriga
3.
How to use Yttriga.
4.
Possible side effects
5.
How to store Yttriga
6.
Further information
1.
WHAT YTTRIGA IS AND WHAT IT IS USED FOR
Yttriga is a radioactive medicine used in combination with another medicine which targets specific
body cells.
When the target is reached, Yttriga gives tiny radiation doses to these specific sites.
For further information regarding the treatment and possible effects caused by the radiolabelled
medicinal product, please refer to the package leaflet of the medicinal product used as combination
partner.
2.
BEFORE YOU USE YTTRIGA
Do not use Yttriga:
- if you are allergic (hypersensitive) to Yttrium (
90
Y) chloride or any of the other ingredients of
Yttriga.
- if you are pregnant or if there is a possibility that you may be pregnant (see below).
Take special care with Yttriga
- Yttriga is a radioactive medicine and is only used in combination with another medicinal product. It
is not intended for direct use in patients.
- Because there are strict laws covering the use, handling and disposal of radiopharmaceuticals,
Yttriga will always be used in a hospital or a similar setting. It will only be handled and
administered by people who are trained and qualified in the safe handling of radioactive material.
Particular care should be taken when administering radioactive medicinal products to children and
adolescents (from 2 to 16 years old).
Taking other medicines
Please tell your doctor or pharmacist, if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
No interaction of Yttrium (
90
Y) chloride with other medicines are known as no clinical studies are
available.
18
Pregnancy and breast-feeding
Women of childbearing potential should use effective contraception during and after treatment. Please
tell your doctor if there is any possibility that you are pregnant. If you have missed a period, you
should assume to be pregnant until a pregnancy test conducted is negative.
Yttriga is contraindicated in Pregnancy.
Your doctor will consider alternative techniques which do not involve ionising radiation.
Your doctor will ask you to stop breast-feeding.
Ask your doctor or pharmacist for advice before taking any medicine.
3.
HOW TO USE YTTRIGA
Your doctor will not administer Yttriga directly.
Dose
Your physician will decide on the amount of Yttriga, which you will receive for the treatment.
Method of administration
Yttriga is intended for radiolabelling of medicinal products to treat specific diseases, which are
subsequently administered by approved route.
If Yttriga is administered inadvertently
Yttriga is administered after being combined with another medicine by your doctor under strictly
controlled conditions. The risk to receive a possible overdose is small. However, should this occur,
you will receive appropriate treatment from your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Yttriga can cause side effects, although not everybody gets them.
For more information, refer to the package leaflet of the particular medicinal product to be
radiolabelled.
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 YTTRIGA
Keep out of the reach and sight of children.
Do not use Yttriga after the expiry date and time which is stated on the label after EXP.
Store in accordance with local regulations for radioactive substances.
Any unused product or waste material should be disposed of in accordance with local requirements.
6.
FURTHER INFORMATION
What Yttriga contains
-
The active substance is Yttrium (
90
Y) chloride.
-
1 ml sterile solution contains 0.1-300 GBq Yttrium (
90
Y) on the reference date and time
(corresponding to 0.005-15 micrograms of Yttrium [
90
Y]) (as Yttrium [
90
Y] chloride).
-
The other ingredient is hydrochloric acid (0.04 M).
19
What Yttriga looks like and contents of the pack
Colourless type I glass vial of 3 ml with a V-shapped bottom or a 10 ml with a flat bottom with a
PTFE faced chlorobytylrubber stopper or silicon stopper, closed with an aluminium seal.
Radiopharmaceutical precursor, solution.
Colourless clears sterile solution.
Marketing Authorisation Holder and Manufacturer
Eckert & Ziegler Nuclitec GmbH
Gieselweg 1,
D-38110 Braunschweig
Germany
Tel +49- 05307-932262
Fax
+49- 05307-932337
e-mail
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web
20
Source: European Medicines Agency
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