SUMMARY OF PRODUCT CHARACTERISTICS. for

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1 SUMMARY OF PRODUCT CHARACTERISTICS for Sodium ( 131 I) Iodide, Injection, GE Healthcare 1. NAME OF MEDICINAL PRODUCT Sodium ( 131 I) Iodide Injection, GE Healthcare 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Sodium ( 131 I) Iodide: MBq/vial (74 MBq/ml) at the activity reference date GBq/vial (925 MBq/ml) at the activity reference date Iodine-131 is produced by fission of Uranium-235 or by neutron bombardment of stable tellurium in a nuclear reactor. It decays by emission of gamma radiations of 365 kev (81.7 %), 637 kev (7.2 %) and 284 (6.1 %) and beta radiations of maximal energy of MeV to stable Xenon-131. Iodine-131 has a half-life of 8.02 days. Excipients with known effect: This medicinal product contains 5.9 mg/ml sodium. To be taken into consideration by patients on a controlled sodium diet. For the full list of excipients, see section PHARMACEUTICAL FORM Solution for injection. Clear, colourless solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic Indications Diagnostic indications Sodium iodide may be given as a tracer dose to study radioiodine kinetics. An estimation of the thyroid uptake and effective half-life obtained with a tracer amount can be used to calculate the activity required for radioiodine therapy. In the management of thyroid carcinoma, sodium iodide is used to identify thyroid remnant and metastases (after ablation). Thyroid scanning for benign conditions with sodium ( 131 I) iodide can be performed but only where circumstances do not allow for radiopharmaceuticals with more favourable dosimetry to be used. Therapeutic indications Radioiodide thyroid therapy is indicated for: Treatment of Graves disease, toxic multinodular goitre or autonomous nodules Treatment of papillary and follicular thyroid carcinoma including metastatic disease.

2 Sodium ( 131 I) iodide therapy is often combined with surgical intervention and with antithyroid medications. 4.2 Posology and method of administration Posology Diagnostic use Adults The recommended activities for an adult patient (70 kg) are as follows: 1. For the thyroid uptake studies: MBq. 2. For identification of metastases and thyroid remnant after thyroid ablation: a maximum dose of 400 MBq. 3. For thyroid imaging: MBq. Scans are usually performed at 4 hours and then again at hours (for scintigraphy also at 72 hours). Elderly Population No dose adjustment is recommended based on age. Renal impairment Careful consideration of the activity to be administered is required since an increased radiation exposure is possible in these patients. Paediatric population The use in children and adolescents has to be considered carefully, based upon clinical needs and assessing the risk/benefit ratio in this patient group. The diagnostic activity to be administered to a child and adolescent should be a fraction of the adult dose calculated from the body weight/surface area methods or according to the following table: Correction factors given for guidance are proposed below. Fraction of adult dose 3 kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = kg = 0.99 (Paediatric Task Group, European Association of Nuclear Medicines)

3 Therapeutic use Adults The activity administered is a matter for clinical judgement. The therapeutic effect is only achieved after several months. For the treatment of hyperthyroidism The activity administered is usually in the range of MBq but repeated treatment may be necessary, with cumulative activities of up to 5000 MBq. The dose required depends on the diagnosis, the size of the gland, thyroid uptake and iodine clearance. Patients should be rendered euthyroid medically whenever possible before giving radioiodine treatment for hyperthyroidism. For thyroid ablation and treatment of metastases: The administered activities following total or sub-total thyroidectomy to ablate remaining thyroid tissue are in the range of MBq. It depends on the remnant size and radioiodine uptake. In subsequent treatment for metastases, administered activity is in the range MBq. After high doses used, e.g. for the treatment of thyroid carcinoma, patients should be encouraged to increase oral fluids to have frequent bladder emptying to reduce bladder radiation. Elderly Population No dose adjustment is recommended based on age. Renal impairment Careful consideration of the activity to be administered is required since an increased radiation exposure is possible in these patients. Paediatric population The use in children and adolescents has to be considered carefully, based upon clinical needs and assessing the risk/benefit ratio in this patient group. The therapeutic activity to be administered to a child over 10 years and adolescent should be a fraction of the adult dose, calculated from body weight or surface area. Method of Administration Sodium Iodide ( 131 I) Injection is for intravenous use. Sodium Iodide ( 131 I) Injection is for multidose use (see section 6.3). For patient preparation, see section Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Established or suspected pregnancy or when pregnancy has not been excluded (see section 4.6). Thyroid scanning, except in the follow up of malignant disease or when sodium [ 123 I] iodide or technetium-99m is not available.

4 4.4 Special warnings and precautions for use Potential for hypersensitivity of anaphylactic reactions: If hypersensitivity or anaphylactic reactions occur, the administration of the medicinal product must be discontinued immediately and intravenous treatment initiated, if necessary. To enable immediate action in emergencies, the necessary medicinal products and equipment such as endotracheal tube and ventilator must be immediately available. Individual benefit/risk justification: For each patient, exposure to ionising radiation must be justifiable by likely benefit. The activity administered should in every case be as low as reasonable achievable to obtain the required diagnostic information or therapeutic effect. Renal impairment In patients with reduced kidney function, careful consideration of the indication is required since an increased radiation exposure is possible in these patients. The administration of high doses of sodium [ 131 I] iodide in patients with significant renal impairment, in which an activity adjustment is necessary, requires special attention. Paediatric population For information on the use in the paediatric population, see section 4.2. Careful consideration of the indication is required since the effective dose per MBq is higher than in adults (see section 11). Patient preparation: The patient should be well hydrated before the start of the examination and urged to void as often as possible during the first hours after the examination in order to reduce radiation. Special precautions, such as urinary catheterisation, should be taken following administration of Sodium Iodide ( 131 I) Injection to patients who are significantly incontinent to minimise risks of radioactive contamination. International guidelines for disposal of radioactive waste must be followed. After high doses used, e.g., for the treatment of thyroid carcinoma, patients should be encouraged to increase oral fluids and urged to void as often as possible to reduce bladder radiation, especially after high activities e.g. for radionuclide therapy. Patients with bladder voiding problems should be catheterised after high activity administration. After the procedure For radioprotection reasons following therapeutic doses, it is recommended to avoid close contact between patient and child for at least one week. Specific warnings: The risk of second primary malignancies in thyroid cancer survivors treated with radioactive iodine is slightly increased compared to thyroid cancer survivors not treated with radioiodine.

5 There is inconclusive evidence of a beneficial effect of saliva stimulation to avoid sialadenitis. A low iodine diet prior to therapy will enhance uptake into functioning thyroid tissue. Thyroid replacement should be stopped prior to radioiodine administration for thyroid carcinoma to ensure adequate uptake. This preparation is likely to result in a relatively high radiation dose to most patients. In the treatment of children over 10 years old and young people, account must be taken of the greater sensitivity of child tissue and the greater life expectancy of such patients. The risks must also be weighed up against those of other possible treatments. Contraception for 6 months (for patients with benign thyroid conditions) or 12 months (for patients with thyroid cancer) is recommended for both sexes after therapeutic administration of sodium [ 131 I] iodide. There is no evidence of an increased incidence of malignancies (cancer, leukaemia or mutations) in man with patients treated for diagnostic purpose with sodium [ 131 I] iodide. This medicinal product contains sodium 5.9 mg per millilitre. This needs to be taken into consideration for patients on a controlled sodium diet. For precautions with respect to environmental hazard see section Interactions with other medicinal products and other forms of interaction Many pharmacological agents are known to interact with radioiodide. These may do so by a variety of mechanisms which can affect the protein binding, the pharmacokinetics or influence the dynamic effects of labelled iodide. It is therefore necessary to take a full drug history and ascertain whether any medications are required to be withheld prior to the administration of sodium [ 131 I] iodide. For example, the treatment with the following substances should be discontinued: Active substances Antithyroid agents (e.g. carbimazole, methimazole, propyluracil), perchlorate Salicylates, steroids, sodium nitroprusside, sodium sulfobromophthalein, anticoagulants, antihistamines, antiparasitics, penicillins, sulphonamides, tolbutamide, thiopental Withdrawal period prior to administration of sodium [ 131 I] iodide. 2 5 days before starting treatment till several days after administration. 1 week.

6 Phenylbutazone Iodine-containing expectorants and vitamins Thyroid hormone preparations Amiodarone*, benzodiazepines, lithium Iodine-containing preparations for topical use Water-soluble iodine-containing contrast media Orale cholecystographic agents 1-2 weeks. approx. 2 weeks. 2 6 weeks. (see section 4.4 for therapeutic recommendations). approx. 4 weeks. 1-9 months. up to 3 months up to 1 year. * Due to the long half-life of amiodarone, iodine uptake in the thyroid tissue can be decreased for several months. 4.6 Fertility, pregnancy and lactation Woman of childbearing potential When an administration of radiopharmaceuticals to a woman of childbearing potential is intended, it is important to determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. If in doubt about her potential pregnancy (if the woman has missed a period, if the period is very irregular, etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient. Women receiving sodium [ 131 I] iodide should be advised NOT to become pregnant within 6 12 months of administration. Contraception in males and females Contraception for 6 months (for patients with benign thyroid conditions) or 12 months (for patients with thyroid cancer) is recommended for both sexes after therapeutic administration of sodium [ 131 I] iodide. Fertility For information regarding impairment of fertility, see section 4.8. Sperm banking should be considered for young men who have extensive disease and therefore may need high radioiodine therapeutic doses. Pregnancy: Sodium [ 131 I] iodide is contraindicated during established or suspected pregnancy or when pregnancy has not been excluded (see section 4.3). The absorbed dose to the uterus for this agent is likely to be in the range of mgy. The foetal thyroid gland avidly concentrates iodine during the second and third trimesters.

7 In the case of differentiated thyroid carcinoma diagnosed in pregnancy therefore, radioiodine treatment should be postponed until after the pregnancy has ended. Alternative techniques which do not involve ionising radiation should be considered. Breastfeeding: Before administering radiopharmaceuticals to a mother who is breastfeeding consideration should be given to the possibility of delaying the administration of radionuclide until the mother has ceased breastfeeding and to what is the most appropriate choice of radiopharmaceuticals, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary, patients should be advised to discontinue breastfeeding for 6 8 weeks before radioiodine administration and therapy must be delayed until lactation ceases, in order to minimize the radiation dose to the breast. Moreover, for radioprotection reasons, it is recommended to avoid close contact between mother and the infant for at least one week (see 4.4). 4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive or use machines have been performed. 4.8 Undesirable effects The frequencies of undesirable effects are defined as follows: Very common ( 1/10), common ( 1/100 to <1/10), uncommon ( 1/1,000 to <1/100), rare ( 1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data) Diagnostic indications Immune system disorders Gastrointestinal disorders Congenital, familial and genetic disorders Hypersensitivity. Nausea, vomiting. Congenital thyroid disorders. Therapeutic indications Blood and the lymphatic system disorders Bone marrow depression, including serious thrombocytopenia, erythrocytopenia and/or leukopenia.

8 Eye disorders Very common: Metabolism and Nutrition disorders Not known Gastrointestinal disorders Very common: Endocrine disorders Very common: Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon: Sicca syndrome, acquired dacryostenosis. Endocrine ophtalmopathy, Hyponatraemia Transient or persistent sialadenitis, including dry mouth, nausea, vomiting. Hypothyroidism. Aggravated hyperthyroidism, Basedow s (Graves ) disease, hypoparathyroidism, hyperparathyroidism. Leukaemia Gastric cancer, bladder and breast cancer. Immune system disorders Reproductive system and breast disorders Congenital, familial and genetic disorders Injury, poisoning and procedural complications Very common: Hypersensitivity. Impairment of fertility in man and woman. Congenital thyroid disorders. Radiation injury, including radiation thyroiditis, radiation associated pain, tracheal obstruction Early consequences Occurrence of radiation caused pneumonia and lung fibrosis has been described in patients with lung metastases. In the treatment of metastasizing thyroid carcinomas with CNS involvement, the possibility of local cerebral oedema and/or an increasing existing cerebral oedema must also be borne in mind. Late consequences Dose dependent hypothyroidism may occur as a late consequence of radioiodine treatment of hyperthyroidism. This may manifest itself weeks or years after treatment, requiring suitable timed measurement of thyroid function and appropriate thyroid replacement therapy. The incidence of hypothyroidism, generally not seen until 6-12 weeks.

9 Malfunction of the salivary and/or lacrimal glands with resulting sicca syndrome may also appear with a delay of several months and up to two years after radioiodine therapy. Also, epiphora due to nasolacrimal duct obstruction mostly appearing 3-16 months after the radioiodine treatment. In a literature report, carcinoma of the salivary glands has been described following radioiodine-induced sialoadenitis. As a late consequence a single administration of over 5000 MBq or an interval of below 6 months are more likely to be associated with reversible or in very rare cases irreversible bone marrow depression developing, with isolated thrombocytopenia or erythrocytopenia, which may be fatal. Radiotherapy of thyroid carcinoma can lead to an impairment of fertility in man and woman. A dose-dependent, reversible impairment of spermatogenesis has been proven starting at doses of 1850 MBq; clinically relevant effects including oligospermia and azoospermia, and increased serum FSH values have been described after use of more than 3700 MBq. Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. For diagnostic use, As the effective dose is 24.4 msv when the maximal recommended activity of 400 MBq is administered (thyroid blockage) these adverse reactions are expected to occur with a low probability. 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. For therapeutic use, radiation dose to specific organs, which may not be the target organ of therapy, can be influenced significantly by pathophysiological changes induced by the disease process. As part of the risk-benefit assessment it is advised that the Effective Dose and likely radiation doses to individual target organ(s) be calculated prior to administration. The activity might then be adjusted according to thyroid mass, biological half-life and the re-cycling factor which takes into account the physiological status of the patient (including iodine depletion) and the underlying physiology. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Norway Statens legemiddelverk Nettside: Overdose This agent is intended for use by competent personnel within a hospital setting. As such the risk of overdose is theoretical. The risks related to the inadvertent administration of excess radioactivity. High radiation exposure through overdose can be reduced by means of administration of thyroid blocking agent, such as potassium perchlorate, the use of the emetics and promoting a diuresis with frequent voiding of urine.

10 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Various thyroid diagnostic radiopharmaceuticals. ATC Code: V09FX03 Pharmacotherapeutic group: Iodine ( 131 I) compounds. ATC Code: V10XA01 Iodide in the amount used for diagnostic and therapeutic indications is not known to have any pharmacological effect. More than 90 % of the radiation effects result from beta radiation which has a mean range of 0.5 mm. 5.2 Pharmacokinetic properties Distribution Following injection, about 20 % of blood iodide is extracted in a single passage through the thyroid gland. Organ uptake Peak thyroid accumulation occurs within hours of dosing with about 50 % of the maximum at 5 hours. This kinetic profile provides the rationale for the diagnostics procedures at 24 and 72 hours after dosing. Elimination Elimination is mainly via the urine. Small amounts of iodide ( 131 I) are taken up by salivary glands, gastric mucosa and would also be localised in breast milk, the placenta and choroids plexus. Urinary excretion is % faecal excretion is about 10 % with almost negligible excretion in sweat. Half-life The effective half-life of radioiodine in plasma is in the order of 12 hours whereas that for radioiodine taken up by the thyroid gland is about 6 days. Thus after administration of sodium ( 131 I) iodide approximately 40 % of the activity has an effective half-life of 0.4 days and the remaining 60 % 8 days. 5.3 Preclinical safety data Because of the small quantities of substance administered compared with the normal food intake of iodine ( mcg/day) no acute toxicity is expected or observed. There are no data available on the toxicity of repeated doses of sodium iodide or on its effects on reproduction in animals or its mutagenic or carcinogenic potential. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium thiosulphate Sodium dihydrogen phosphate Disodium hydrogen phosphate Sodium chloride Sodium hydroxide

11 Water for Injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 28 days from the activity reference date stated on the label. Once opened store in refrigerator (2ºC-8ºC) and use within 8 hours. Since the product does not contain an antimicrobial preservative and is marketed for multidose use, all doses from a single vial should be taken within a single working day and the product stored at (2ºC-8ºC) after removal of the first aliquot. 6.4 Special precautions for storage Store below 25 o C. Do not freeze. For storage conditions after first opening of the medicinal product, see section 6.3. Storage of radiopharmaceuticals should be in accordance with national regulations on radioactive materials. 6.5 Nature and contents of container The product is supplied in a Type 1 neutral, clear 10 ml glass vial sealed with a PTFEfaced butyl rubber closure and aluminium overseal. Each vial is packed within a radiation shielding container of lead metal and placed within a sealed metal tin. Pack size: 74 MBq - pack sizes range from 37 MBq to 740 MBq 925 MBq - pack sizes range from 925 MBq to 9250 MBq Not all pack sizes may be marketed 6.6 Special precautions for disposal and other handling General warning Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the competent official organisation. Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. If at any time in the preparation of this product the integrity of the container is compromised it should not be used. Administration procedures should be carried out in a way to minimise risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

12 The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spill of urine, vomiting etc. Radiation protection precautions in accordance with national regulations must therefore be taken. Any unused product or waste material should be disposed of in accordance with local requirements for radioactive material. 7. MARKETING AUTHORISATION HOLDER GE Healthcare Limited Amersham Place Little Chalfont Buckinghamshire HP7 9NA United Kingdom 8. MARKETING AUTHORISATION NUMBER 74 MBq MTnr: MBq MTnr: DATE OF FIRST AUTHORISATION DATE OF REVISION OF THE TEXT DOSIMETRY The table below shows the shows the dosimetry as calculated according to the publication 53 and 60 of the ICRP (International Commission of Radiological Protection, Radiation Dose to Patients from Radiopharmaceuticals). For diagnostic use The effective dose resulting from an administration of a (maximal recommended) activity of 400 MBq for diagnostic use is typically between 24.4 msv (0 % thyroid uptake) and msv (55 % thyroid uptake). For therapeutic use Radiation dose to specific organs, which may not be the target organ of therapy, can be influenced significantly by pathophysiological changes induced by the disease process. As part of the risk-benefit assessment it is advised that the effective dose and likely radiation doses to individual target organ(s) be calculated prior to administration. The activity might then be adjusted according to thyroid mass, biological half-life and the recycling factor which takes into account the physiological status of the patient (including iodine depletion) and the underlying pathology.

13 IODIDE Thyroid blocked, uptake 0 % Absorbed dose per unit activity administered (mgy/mbq) Organ Adult 15 Year 10 Year 5 Year 1 Year Adrenals Bladder wall Bone surfaces Breast GI tract Stomach wall Small intest ULI wall LLI wall Kidneys Liver Lungs Ovaries Pancreas Red marrow Spleen Testes Thyroid Uterus Other tissue Effective Dose (msv/mbq) Bladder wall contributes to 50.0% of the effective dose. Incomplete blockage: Effective dose (msv/mbq) at small uptake in the thyroid. uptake: 0.5% uptake 1.0% uptake 2.0%

14 Thyroid uptake 15 % Absorbed dose per unit activity administered (mgy/mbq) Organ Adult 15 Year 10 Year 5 Year 1 Year Adrenals Bladder wall Bone surfaces Breast GI tract Stomach wall Small intest ULI wall LLI wall Kidneys Liver Lungs Ovaries Pancreas Red marrow Spleen Testes Thyroid Uterus Other tissue Effective Dose (msv/mbq)

15 Thyroid uptake 35 % Absorbed dose per unit activity administered (mgy/mbq) Organ Adult 15 Year 10 Year 5 Year 1 Year Adrenals Bladder wall Bone surfaces Breast GI tract Stomach wall Small intest ULI wall LLI wall Kidneys Liver Lungs Ovaries Pancreas Red marrow Spleen Testes Thyroid Uterus Other tissue Effective Dose (msv/mbq)

16 Thyroid uptake 55 % Absorbed dose per unit activity administered (mgy/mbq) Organ Adult 15 Year 10 Year 5 Year 1 Year Adrenals Bladder wall Bone surfaces Breast GI tract Stomach wall Small intest ULI wall LLI wall Kidneys Liver Lungs Ovaries Pancreas Red marrow Spleen Testes Thyroid Uterus Other tissue Effective Dose (msv/mbq) INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS The product is an aqueous solution for intravenous injection and should be used according to section 4.2.