YTTRIGA 0.1-300GBq / ml solution medication leaflet

Yttriga radiopharmaceutical precursor, solution.

1 ml sterile solution contains 0.1-300 GBq Yttrium (90Y) on the reference date and time(corresponding to 0.005-15 micrograms of Yttrium [90Y]) (as Yttrium [90Y] chloride).

Each 3ml vial contains 0.1-300 GBq, corresponding to 0.005-15 micrograms of Yttrium (90Y), atreference date and time. The volume is 0.02-3 ml.

Each 10ml vial contains 0.1-300 GBq, corresponding to 0.005-15 micrograms of Yttrium (90Y), atreference date and time. The volume is 0.02-5 ml.

The theoretical specific activity is 20 GBq/microgram of Yttrium (90Y) (see section 6.5).

Yttrium (90Y) chloride is produced by decay of its radioactive precursor Strontium (90Sr). It decays byemission of beta radiation of 2.281 MeV (99.98 %) of maximal energy to stable Zirconium (90Zr).

Yttrium (90Y) has a half-life of 2.67 days (64.1 hours).

For a full list of excipients, see section 6.1.

Radiopharmaceutical precursor, solution.

Clear colourless solution, free of particulate matter.

To be used only for the radiolabelling of carrier molecules, which have been specifically developedand 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.

The quantity of Yttriga required for radiolabelling and the quantity of Yttrium (90Y)-labelled medicinalproduct that is subsequently administered will depend on the medicinal product radiolabelled and itsintended use. Refer to the Summary of Product Characteristics/package leaflet of the particularmedicinal product to be radiolabelled.

Yttriga is intended for in vitro labelling of medicinal products which are subsequently administered bythe approved route.

Further information on the preparation of the product is given in section 12.

Do not administer Yttriga directly to the patient.

Yttriga is contraindicated in the following cases:

- Hypersensitivity to Yttrium (90Y) chloride or to any of the excipients

Yttrium (90Y)-labelled medicinal products are contraindicated in the following case:

- Established or suspected pregnancy or when pregnancy has not been excluded (see section 4.6)

For information on contraindications to particular Yttrium (90Y)-labelled medicinal products preparedby radiolabelling with Yttriga refer the Summary of Product Characteristics/package leaflet of theparticular 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 forthe radiolabelling of carrier molecules, such as monoclonal antibodies, peptides or other substrates.

Radiopharmaceuticals should be received, used and administered only by authorised persons indesignated clinical settings and receipt, storage, use, transfer and disposal are subject to the regulationsand appropriate licences of the competent authorities.

Radiopharmaceuticals should be prepared by the user in a manner which satisfies both radiation safetyand pharmaceutical quality requirements.

For information concerning special warnings and special precautions for use of Yttrium (90Y)-labelledmedicinal products refer to the Summary of Product Characteristics/package leaflet of the medicinalproduct to be radiolabelled.

Particular care should be taken when administering radioactive medicinal products to children andadolescents (from 2 to 16 years old).

No interaction studies of Yttrium (90Y) 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 (90Y)-labelled medicinalproducts refer to the Summary of Product Characteristics/package leaflet of the medicinal product tobe radiolabelled.

Women of childbearing potential have to use effective contraception during and after treatment.

Yttrium (90Y)-labelled medicinal products are contraindicated in established or suspected pregnancy orwhen pregnancy has not been excluded (see section 4.3).

Before administering a radioactive medicinal product to a mother who is breast-feeding, considerationshould be given to whether the investigation could be reasonably delayed until the mother has ceasedbreast-feeding. If the administration cannot be delayed, a lactating mother should be advised to stopbreast-feeding.

Further information concerning the use of a Yttrium (90Y)-labelled medicinal products in pregnancyand breast-feeding is specified in the Summary of Product Characteristics of the medicinal product tobe radiolabelled.

Further information concerning the use of a Yttrium (90Y)-labelled medicinal concerning fertility isspecified 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 (90Y)-labelledmedicinal products will be specified in the Summary of Product Characteristics/package leaflet of themedicinal product to be radiolabelled.

Possible adverse reactions following the intravenous administration of a Yttrium (90Y)-labelledmedicinal product prepared by radiolabelling with Yttriga, will be dependent on the specific medicinalproduct 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, exposureto ionising radiation must be justifiable on the basis of likely clinical benefit. The activity administeredmust be such that the resulting radiation dose is as low as reasonably achievable bearing in mind theneed to obtain the intended therapeutic result.

Exposure to ionising radiation is linked with cancer induction and a potential for development ofhereditary defects.

The radiation dose resulting from therapeutic exposure may result in higher incidence of cancer andmutations. In all cases, it is necessary to ensure that the risks of the radiation are less than from thedisease itself.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The presence of free Yttrium (90Y) chloride in the body after an inadvertent administration of Yttrigawill lead to increased bone marrow toxicity and haematopoietic stern cell damage.

Therefore, in case of an inadvertent administration of Yttriga, the radiotoxicity for the patient must bereduced 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 ofcarrier molecules for therapeutic purposes:

- Ca-DTPA (Trisodium calcium diethylenetriaminepentaacetate) or

- Ca-EDTA (Calcium disodium ethylenediaminetetraacetate)

These chelating agents suppress yttrium radiotoxicity by an exchange between the calcium ion and theyttrium 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 orby 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 iscirculating in or available to tissue fluids and plasma. However, a post-exposure interval > 1 hour doesnot preclude the administration and effective action of chelator with reduced efficiency.

Intravenous administration should not be protracted over more than 2 hours.

In any case the blood parameters of the patient have to be monitored and the appropriate actionsimmediately taken if there is evidence of damage to the blood marrow.

The toxicity of the free Yttrium (90Y) due to in-vivo release from the labelled biomolecule in the bodyduring therapy could be reduced by post-administration of chelating agents.

Pharmacotherapeutic group: Other therapeutic radiopharmaceuticals, ATC code: V10X.

The pharmacodynamic properties of Yttrium (90Y)-labelled medicinal products prepared byradiolabelling with Yttriga, prior to administration, will be dependent on the nature of the medicinalproduct to be radiolabelled. Refer to the Summary of Product Characteristics/package leaflet of theparticular medicinal product to be radiolabelled.

The pharmacokinetic properties of Yttrium (90Y)-labelled medicinal products prepared byradiolabelling with Yttriga, prior to administration, will be dependent on the nature of the medicinalproduct to be radiolabelled.

In the rat, following intravenous administration, Yttrium (90Y) chloride is rapidly cleared from theblood. At 1 and 24 hours, blood radioactivity decreases from 11.0 % to 0.14 % of the administeredactivity. The two main organs where Yttrium (90Y) chloride distributes are the liver and bones. In theliver, 18 % of the injected activity is taken up 5 min after injection. Liver uptake decreases then to8.4 % 24 hours after injection. In bone, percentage of injected activity increases from 3.1 % at 5 minto 18 % at 6 hours and then decreases with time. Faecal and urinary elimination is slow: about 31 % ofthe administered activity is eliminated in 15 days.

The toxicological properties of Yttrium (90Y)-labelled medicinal products prepared by radiolabellingwith Yttriga prior to administration, will be dependent on the nature of the medicinal product to beradiolabelled.

There are no data available on the toxicity of Yttrium (90Y) chloride nor on its effects on reproductionin animals or its mutagenic or carcinogenic potential.

Hydrochloric acid (0.04 M)

Radiolabelling of medicinal products, such as monoclonal antibodies, peptides or other substrates,with Yttrium (90Y) chloride is very sensitive to the presence of trace metal impurities.

It is important that all glassware, syringe needles etc, used for the preparation of the radiolabelledmedicinal product are thoroughly cleaned to ensure freedom from such trace metal impurities. Onlysyringe needles (for example, non-metallic) with proven resistance to dilute acid should be used tominimise trace metal impurity levels.

Up to 12 days from the date of manufacture.

Storage should be in accordance with national regulation on radioactive material.

Colourless type I glass vial of 3 ml with a V-shapped bottom or a colourless type I glass vial of 10 mlwith a flat bottom with a silicon stopper, closed with an aluminium seal.

Pack size: 1 vial

Not all presentations may be marketed.

The vial may contain high pressure due to radiolysis (see section 12).

Eckert & Ziegler Radiopharma GmbH

Robert-Rössle-Str. 10

D-13125 Berlin

Germany

EU/1/05/322/001 (3 ml V-shaped vial)

EU/1/05/322/002 (10 ml flat bottom vial)

Date of first authorisation: 19/01/2006

Date of renewal: 06/01/2011

The radiation dose received by the various organs following intravenous administration of an

Yttrium (90Y)-labelled medicinal product is dependent on the specific medicinal product beingradiolabelled. Information on radiation dosimetry of each different medicinal product followingadministration 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 (90Y) to the radiation dose following the administration of Yttrium (90Y)-labelled medicinalproduct or resulting from an accidental intravenous injection of Yttriga.

The dosimetry estimates were based on a rat distribution study and the calculations were effected inaccordance with MIRD/ICRP 60 recommendations. Time-points for measurements were 5 min, 1, 6,24, 96 and 360 hours.

Absorbed dose per unit activity administered (mGy/MBq)

Organ Adult 15 years 10 years 5 years 1 year Newborn(70 kg) (50 kg) (30 kg) (17 kg) (10 kg) (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-intestinalcontent 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 of1 GBq is 665 mSv.

Before use, packaging and radioactivity should be checked. Activity may be measured using anionisation chamber. Yttrium (90Y) is a beta pure emitter. Activity measurements using an ionisationchamber are very sensitive to geometric factors and, therefore, should be performed only undergeometric 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 beaseptically withdrawn through the stopper using sterilised single use needle and syringe afterdisinfecting 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 maintainsterility throughout the labelling procedures.

The administration of radioactive medicinal products creates risks for other persons from externalradiation or contamination from spills of urine, vomiting, etc. Radiation protection precautions inaccordance with national regulations must therefore be taken.

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 Agencyhttp://www.ema.europa.eu