Summary of Product Characteristics

1. NAME OF THE MEDICAL PRODUCT

I-131-sodium iodide capsule for diagnostic and therapeutic purposes (I-RA-7/k)

Gelatine capsule, administerable per os (orally), dissolving in the stomach. It contains the non carrier added I-131-sodium iodide in adsorbed form.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

Gelatine capsule dissolving in the stomach

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

This medical product, depending on the administered activity, is both for ISOTOPE DIAGNOSTICS and RADIONUCLIDE THERAPY of the following diseases

DIAGNOSTIC EXAMINATIONS:

– iodine uptake studies of the thyroid
– localization and morphology of the thyroid
– determination of the regional thyroid function
– determination of hyperthyreosis or hypothyreosis
– determination of toxic adenoma, autonom adenoma or thyroid carcinoma

THERAPEUTIC TREATMENTS

a) Hyperthyreosis:

Radionuclide therapy of the hyperfunction, decrease of the size of the thyroid.

– Treatment of Basedow disease
– Treatment of hyperfunction adenomas
– Treatment of non-immunogene, diffuse goitre

b) Thyroid carcinoma:

Radionuclide therapy treatment

– Destruction of the remaining thyroid tissues after the operation of the thyroid (ablation)
– Treatment of recidives and metastases

4.2 Posology and mode of administration

IN DIAGNOSTIC STUDIES: 1 - 4 MBq/patient

IN THERAPEUTIC TREATMENTS:

a) Treatment of hyperthyreosis

The administerable activity is to be calculated from the recommended absorbed dose with the following formula (On the other hand an activity originating from and determined by other recommendations may also be administered).

Recommended absorbed dose values:
– For treatment of Basedow disease: 40-80 Gy
– For treatment of hyperfunction adenoma: 300-400 Gy
– For treatment of non-immunogen, diffuse goitre: 150-200 Gy

Activity to be administered: A (MBq)

A (MBq) = [25 × M (g) × D (Gy) ] / [ F_max (%) × T_eff (day) ]

where M is the mass of the thyroid in grams, which is to be calculated from the scintigram by the planimetry method:

Activity values applied for treatment of hyperthyreosis usually fall in the range of 50 MBq – 1 GBq.

b) Treatment of thyroid tumour:

Mode of administration:

The required activity, in both diagnostic studies and therapeutic treatments, is introduced into the body by administering 1 or maximum 2 capsules per os (orally).

4.3 Contraindications

IN DIAGNOSTIC STUDIES:

RELATIVE CONTRAINDICATIONS

The use of the product is relatively contraindicated

– At the age below 18 years,
– in case of pregnant or lactating women

except when the necessity and importance of the treatment prevails the risk originating from the radiation exposure.

ABSOLUTE CONTRAINDICATIONS

The use of the product is absolutely contraindicated

– if the patient does not provide an oral or written consent of being examined by radioisotopes.

IN THERAPEUTIC TREATMENTS:

RELATIVE CONTRAINDICATIONS

The use of the product is relatively contraindicated

– at the age below 18 years

except when the necessity and importance of the treatment prevails the risk originating from the radiation exposure.

ABSOLUTE CONTRAINDICATIONS

The use of the product is absolutely contraindicated

– in case of pregnant or lactating women,
– if the patient does not provide an oral or written consent of being treated by radionuclide therapy.

4.4 Special warnings and special precautions for use

The product is a radioisotope containing pharmaceutical. The rules for handling, transportation and storage of radioactive materials are applicable for the product.

The pharmaceutical can only be applied by properly qualified and trained personnel within designated clinical settings, which possess the appropriate government authorisation for the use and manipulation of radioisotopes.

The treatment of hyperthyreosis can be carried out in ambulant way as well. Such in case the relevant international and national prescriptions and regulations should be taken into consideration concerning the patient’s way of living are to be kept (mode of traffic, urination, living with family members, etc.).

The radionuclide therapy treatment of thyroid tumor can only be carried out in a designated health institute (hospital, clinic) with taking consideration of the relevant regulations.

4.5 Interactions with other medicinal products and other forms of interaction

Hindered I-131 uptake is disadvantageous both in case of thyroid scintigraphy and thyroid radionuclide therapy, therefore, introduction of inactive iodine is to be avoided. Such treatments are to be terminated prior to the administration of radioiodide according to the following table:

The clearance of radioiodide from the thyroid - in case of necessity - can be slowed down with lithium-carbonate. Colchicin also reduces the radioiodide clearance rate.

4.6 Application during pregnancy and lactation

Application of the product during pregnancy and lactation is contraindicated.

4.7 Effect of the product on ability to drive and on working in circumstances of significant accident risk

The product has no direct influence on ability of car driving or working in hazardous circumstances. In occurrence of unexpected side effects the ability to drive and the aptitude to work amidst accident risk are to be reconsidered.

4.8 Undesirable effects

Occurrence of undesirable effects and symptoms is unexpected.

4.9 Overdose

There is no information available about any actually occurred overdose.
Administration of higher activity than prescribed results in unnecessary absorbed radiation dose on the patient and her/his environment, which is to be avoided.

Administration of higher activity than necessary may cause hypothyreosis.
In occurrence of an eventual overdose the effective absorbed radiation dose is to be calculated with using the dosimetry table of the section 5.4 and the decision about the necessity and mode of further treatments are to be made based on the result.

5. PHARMACOLOGICAL PROPERTIES

ATC-codes: diagnostics V09F X 03; therapeutics V10X A 01

5.1 Pharmacodynamic properties

Iodine is a microelement of vital importance, which is inevitably necessary to the synthesis of the metabolism regulating thyroid hormones.

90% of I-131-sodium-iodide introduced into the body gets to the blood within an hour and 100% of it within 4 hours. From the circulation system it runs to the thyroid, appears in the salivary glands, the placenta and it is excreted by the plexus chorioideus and the mucous membrane of the stomach. In case of lactating women it appears in the milk as well.

In normal case the body takes up approximately 100-500 µg iodine per day with the food, the optimum quantity is 150-300 µg per day (1). Adults’ minimum daily requirement is 100 µg (2). Approximately 10-60% (mostly 20-30%) of the introduced iodine quantity concentrates in the adults’ thyroid of 20 g weight in average, where it is built in the thyroid hormones and their precursors. The iodine concentration of the thyroid depends upon how extensively the satisfaction of the iodine demand is supported by the iodination of the foodstuff. In Hungary 414 ± 280 µg/g thyroid value is common (3).

The specific activity of I-131 is at least 1 GBq/µg, therefore, even in case of administering the maximum recommended therapy dose (7.4 GBq) only 7.4 µg is introduced into the body. Comparing this value to the normal iodine intake data it is obvious that the therapy is not carried out by the pharmacokinetic effect of the chemical iodine quantity but it is the consequence of the energy and transmitted to the tissue during the absorption of the beta-particles emitted by I-131 nuclide, which is devoted to the destruction of the thyroid cells.

In normal case radioiodine washes out from the body with the urine.

5.2 Pharmacokinetic properties

90% of I-131-sodium-iodide introduced into the body per os gets to the bloodstream within an hour and 100% of it within 4 hours.

The kinetics of the radioiodine uptake in the thyroid highly depends on the degree of the iodine supply of the area where the patient lives. For the normal case:

In places of medium degree of iodine supply 20 ± 9% of the activity appears in the thyroid 2 hours after administration. After 6 hours 32 ± 12% is taken up, while the maximum activity (43 ± 11%) after 24 hours. Only 40 ± 10% is the uptake 48 hours subsequent to the administration.

In case of patients with iodine deficiency the uptake is extensive and fast: 80% after 12-18 hours. No wash out can be observed during the first 24 hours.

In hyperthyreosis, due to the increased hormone production, both the uptake and the wash-out are faster: The uptake can reach 80% within 2-6 hours from the introduction, while the wash out is 50% and then 70% after 24 and 48 hours, respectively.

In hypothyreosis and in acute inflamed condition of the thyroid the uptake is of small extent and rate: hardly reaches 20% after 48 hours.

The biological half life of the wash out of I-131 from the body is 4 days in normal case, 1-3 days in hyperthyreosis.

5.3 Preclinical safety data

LD₅₀ value, which expresses the acute toxicity of I-131 introduced orally into the body is 1000 mg/kg body weight for mice and 760 mg/kg body weight for dogs (4). The optimum daily iodine requirement of adult humans is 0.15-0.30 mg/day (1). Since the specific activity of I-131-sodium-iodide is minimum 1 GBq/µg, the maximum iodine content of the highest possible dose administered to a patient (7.4 GBq) cannot exceed 7.4 µg, which is at most 2.4-4.9% of the optimum iodine intake. Therefore, it is obvious that the product can be considered safe in regard of iodine intake.

5.4 Radiophysical properties of the radionuclide and the absorbed doses

The absorbed dose values caused by the introduced I-131-Sodium-iodide in function of the maximum uptake in the thyroid are shown in the following table (5):

The I-131 product can contain radionuclide impurities only in quantity less than 0.1%.

References:

6. PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

6.2 Incompatibilities

Hindered I-131 uptake is disadvantageous both in case of thyroid scintigraphy and thyroid radionuclide therapy, therefore, introduction of inactive iodine is to be avoided. Such treatments are to be terminated prior to the administration of radioiodide according to the following table:

The clearance of radioiodide from the thyroid – in case of necessity – can be slowed down with lithium-carbonate. Colchicin also reduces the radioiodide clearance rate.

From chemical point of view, the product is incompatible with moisture, water and liquids because they moisten and soften the capsule, which results in opening the capsule, falling out the content and finally radioactive contamination.

Especially incompatible the product with acids because in their presence radioiodide is converted into a volatile form (radical or elemental iodine), which – getting to the air – may cause a widespread radioactive contamination in the environment.

Furthermore, the product is incompatible with oxidising agents since they oxidise the present radioiodide (oxidation degree: -1) into elementary radioiodine (oxidation degree: 0), moreover, iodate (oxidation degree: +5) and periodate (oxidation degree: +7) ions may appear. Such components count as radiochemical impurities of the product, their formation is to be avoided.

6.3 Shelf life

21 days from the day of production.

6.4 Special precautions for storage

The product is to be stored at room temperature (15-25°C); free from moisture, humidity, acidic vapours and oxidative agents; using appropriate radiation shielding. Storage conditions should be in accordance with the national regulations on radioactive materials.

6.5 Nature and composition of the packaging

The I-131-sodium-iodide containing therapeutic capsule is supplied in a shielded, screw capped plastic vial. Dimensions: internal diameter 8 mm, height 25 mm. Both the lower and the upper part of the vial are fixed in half-containers made of lead. Upon closing the vial by screwing the cap the half-containers form an entire cylinder-shaped container, which serves as radiation shielding. The wall thickness of the shielding varies between 15 and 30 mm according to the activity of the capsule contained. The labelled lead container is put in a sealed and labelled metal can containing plastic foam spacers. The can can be easily opened by tearing the top panel.

The packaging always contains one capsule.

6.6 Instruction for use and handling

a) Opening the packaging of the radioactive product

Tear off the top panel of the metal can. Remove the upper part of the plastic foam spacer. Lift the lead container out of the metal can and put it on the working area. There are two ways of opening the lead container for two different purposes: activity checking with closed vial without taking out the capsule or opening the plastic vial with the same movement for taking out the capsule.

Opening the lead pot for activity checking:

Manipulate behind the appropriate radiation shielding. Hold the lower part of the lead pot firmly with one hand and pull apart the upper part towards axial direction strongly but evenly by holding it with the other hand. The internal plastic vial will remain fixed in the upper part of the lead pot but its lower part will not be covered by the lead shielding. In this position the activity check can be performed by a laboratory activity measuring unit (dose calibrator) without taking out the capsule from the vial. After measuring put the parts of the lead container together again.

Opening the lead pot and the internal plastic vial at the same time:

Hold the container in vertical position. Screwing the upper part of the lead pot counter-clockwise both the lead container and the plastic vial will open. The upper part of the plastic vial remains in the upper part of the lead pot, while the lower part of the vial, which contains the capsule, remains in the lower part of the lead container. The capsule can be easily taken out (see next paragraph).

b) Mode of administration

Expediently, the patient takes the lower part of the lead pot containing the capsule and takes in the capsule directly from the container by pouring it to the mouth.

7. MARKETING AUTHORISATION HOLDER

Institute of Isotopes Co., Ltd..
1121 Budapest, Konkoly Thege Miklós út 29-33.
1535 Budapest, P.O.B. 851.

8. NUMBER OF THE MARKETING AUTHORISATION

6814/46/95

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Original Marketing Authorisation: August 16^th, 1995

10. DATE OF REVISION OF THE TEXT

February 18^th, 2002