1. NAME OF THE MEDICINAL PRODUCT

I-131-m-Iodine-benzyl-guanidine injection (I-131-MIBG) for therapy purposes (I-RAO-2)

Radioactive injection for intravenous application containing meta-iodine-benzyl-guanidine labelled with I-131 radionuclide.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

Sterile, radioactive injection

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Field of indication: Radionuclide therapy

Local, lesion specific treatment of neuroendocrine tumours, especially:

– phaeochromocytoma
– neuroblastoma
– paraganglioma
– medullary thyroid carcinoma
– carcinoid

4.2 Posology and mode of administration

Dose: 3.3 – 4.1 GBq ¹³¹I-MIBG for one patient. Before beginning with the examination blockage of the thyroid is recommended to prevent uptake of free radioiodine evolving in vivo.

The ampoule containing 3.3-4.1 GBq activity represents a single dose of a patient. The injection is to be administered slowly, during 2-4 hours, therefore the product is not injected directly but its volume of 10 ml is mixed with 90 ml of 5% glucose infusion and the total volume of 100 ml is administered slowly. Introduction of MIBG at once may cause blood pressure increase, allergic symptoms, flushing or asthmatic spasms.

The MIBG-therapy can be monitored with an imaging technique, the gamma camera pictures are usually taken in the 24^th, 48^th, 72^nd and 96^th hour after administration.

4.3 Contraindications

RELATIVE CONTRAINDICATIONS

The use of the product is relatively contraindicated

– At the age below 18 years, except the indication of neuroblastoma

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 with 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 to 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.

4.5 Interactions with other medicinal products and other forms of interaction

Calcium channel blocking agents, labetalol, reserpine, tricyclic anti-depressants, phenyl-propanolamine and cimetidine may impede the MIBG uptake, therefore, their application is to be suspended before carrying out the examination.

4.6 Application during pregnancy and lactation

Application of the product during pregnancy and lactation is definitely and absolutely 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 expectable if the injection is administered faster than prescribed in paragraph 4.2. Such in case blood pressure increase, allergic symptoms, flushing or asthmatic spasms may occur to extremely different extent patient by patient.

4.9 Overdose

There is no information available about any actually occurred overdose. Should still such a case occur treatment should be directed towards the support of vital functions.

Administration of higher activity than prescribed results in unnecessary absorbed radiation dose on the patient and her/his environment, which is to be avoided.

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.

Pursuant to intravenous acute toxicity experiments on mice no clinical symptoms can be observed up to 1.8 mg/kg body. If administered as prescribed maximum 6 mg MIBG is introduced to the body, which is only 4.8% of the mentioned symptom free limit - calculated with an average body weight of 70 kg. In case as the result of an error or a mistake of the personnel the content of two vials are injected, it represents only 9.6% of the symptom free limit. Therefore, not the MIBG content but the overdose of the radioactivity represents the relevant risk.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC-code: V10X A 02

Hormones produced by the adrenal medulla take part in the synthesis and storage of catecholamine. Neuroendocrine tumours (phaeochromocytoma, neuroblastoma, paraganglioma, medullary thyroid carcinoma, carcinoid) consist of cells of analogous nature with those of the adrenal medulla tissue. They excrete hormones specific to the adrenal medulla. Due to the functional similarity of the adrenergic neurones and the chromaffin cells of the adrenal medulla the molecules that are able to bind to the receptors of the adrenergic terminal filaments are of anti-adrenergic effect and they tend to be accumulated by the cells of the adrenal medulla or other cells of similar type. Therefore, bretylium, guanethidine and MIBG, which bears functional groups analogous to them, are expected to bind to neuroendocrine receptors.

Since radioiodine labelled bretylium is unstable and guanethidine can only be labelled with carbon, nitrogen or hydrogen isotopes while MIBG can be labelled with radioiodine easily the latter has been introduced to the clinical practice. ¹³¹I-MIBG strongly binds to the chromaffin cells of the adrenal medulla and the uptake is proportional to the density of the neuroendocrine receptors present. The MIBG uptake may be hindered by cocaine and desmethyl-imipramine.

In aware of the maximum quantity of MIBG (6 mg) and activity (3.3-4.1 GBq) administered it is obvious that the therapy effect is not caused by the pharmacodynamic features of MIBG but it is a result of the energy of the beta particles emitted by ¹³¹I radionuclide, which is transmitted at their absorption in the tissues and destroys the cells.

¹³¹I-MIBG leaves the body with the urine: 82% as intact ¹³¹I-MIBG, 16% as metabolised to meta-iodine-hippuric acid and 2% as free radioiodine.

5.2 Pharmacokinetic properties

10-15% of ¹³¹I-MIBG introduced into the body appears in the cells with functional relationship with the adrenal medulla tissues. 1 hour after administration ¹³¹I-MIBG appears in the lungs, which it leaves in 1-2 hours and binds to the neuroendocrine receptors of the myocardium. The maximum radioactivity in the heart-muscle is observable 2-3 hours after administration, after 24 hours in the adrenal glands, while ¹³¹I-MIBG accumulates in the neuroendocrine tumours and metastases after 24-96 hours.

¹³¹I-MIBG not bound to the receptors leaves the body through the kidneys and the urinary bladder (55% within 24 hours and 90% within 4 days).

5.3 Preclinical safety data

Pursuant to acute toxicity studies* on mice no clinical symptoms are observed up to 20 times of the usual human dose (1.8 mg/kg body weight). The quantity of the maximum dose of ¹³¹I-MIBG prescribed in the Composition and Posology sections (6 mg / 70 kg body weight, i.e. 0.0857 mg/kg) represents only 4.8% of the symptom free limit. Therefore the application of the product is considered safe.

* Radiopharmaceuticals product specification, Isopharma AS, Institutetveien 18, N2007 Kjeller, Norway, 1996, p74.

5.4 Radiophysical properties of the radionuclide and the absorbed dose values

The absorbed dose values caused by the introduced ¹³¹I-MIBG are shown in the following table – calculated with the average body weight (70 kg):

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

6.2 Incompatibilities

Above all, the product is incompatible with oxidising agents and chloride ions because they assist the elimination of radioiodine from ¹³¹I-MIBG molecule. For the same reason the product is to be kept frozen at –18°C. Furthermore, another hazard of the strongly acidic medium that such in circumstances the forming iodine is present in volatile status (radical or elementary iodine), which may cause radioactive contamination in the environment when opening the ampoule.

6.3 Shelf life

5 days from the day of production.

6.4 Special precautions for storage

The product is to be stored in a freezer at -18°C; free from 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

¹³¹I-MIBG solution is supplied in a so called lyophilising glass vial of 6 ml or 12 ml volume, closed with a rubber plug and an aluminium cap. A labelled lead pot, which is capped with a lead cover and lined with a paper cylinder as spacer, serves as radiation shielding. The glass vial is placed in the paper cylinder and this way in the lead container as well. The wall thickness of the lead pot varies between 15 and 30 mm according to the activity of the solution 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.

During delivery the frozen state is assured with cooling the package with dry ice.

6.6 Instruction for use and handling

The product is a radioactive preparation, which should be opened truly according the following instructions:

During the operation the radiation safety regulations should be kept.

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. Remove the seal strip and then the upper part of the lead pot. This way the glass vial containing the radioactive material is readily accessible.

Before beginning with the examination blockage of the thyroid is recommended to prevent uptake of free radioiodine evolving in vivo.

The ampoule containing 3.3-4.1 GBq activity represents a single dose of a patient. The injection is to be administered slowly, during 2-4 hours, therefore the product is not injected directly but its volume of 10 ml is mixed with 90 ml of 5% glucose infusion and the total volume of 100 ml is administered slowly. Introduction of MIBG at once may cause blood pressure increase, allergic symptoms, flushing or asthmatic spasms.

The MIBG-therapy can be monitored with imaging techniques, the gamma camera pictures are usually taken in the 24^th, 48^th, 72^nd and 96^th hour after administration.

Radiochemical purity of ¹³¹I-MIBG should be examined as follows:

Drop 15 µl of ¹³¹I-MIBG solution on each of three Polygram-SIL NHR strips of 1.5×20 cm size 1.5 cm from the end. With using ethylacetate-ethanol mixture (1:1) as eluent let the front run approximately up to 12-15 cm. Then dry the chromatograms, coat them with approx. 5% polystyrene solution and after drying them again the distribution of the radioactivity is determined by a gamma scanner with moving table.

Approximate Rf values:

¹³¹I-MIBG: 0.05-0.15
Free ¹³¹I: 0.80-1.00

Radiochemical purity is calculated with considering the peak areas. Taking the total activity on the strip as 100% the activity ratio corresponding to the peak of ¹³¹I-MIBG provides the radiochemical purity data, which must be minimum 90% at expiry.

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

5512.46./1993.

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Original Marketing Authorisation:    June 28^th, 1993

10. DATE OF REVISION OF THE TEXT

February 6^th, 2003