1. NAME OF THE MEDICINAL PRODUCT

Fyton (sodium-phytate) in vivo kit for preparation of radiopharmaceutical product (Tc-IK-2)

The pharmaceutical is to be prepared on the location of use (hospital or clinical laboratory) by mixing the content of the product and Tc-99m-pertechnate eluate gained from any licensed Mo-99 / Tc-99m isotope generator.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

a.) Composition of Fyton in vivo kit:

b.) Composition of Tc-99m-Fyton radioactive injection:

3. PHARMACEUTICAL FORM

Pharmaceutical form of Fyton in vivo kit: Powder for injection
Pharmaceutical form of Tc-99m-phytate: Radioactive, sterile injection

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

This medical product is for DIAGNOSTIC purposes only.

Field of indication: liver scintigraphy
– Morphology examination of the liver with imaging technique
– Revealing benign and malignant liver tumors and their treatment monitoring

4.2 Posology and mode of administration

The quantity of Tc-99m-Fyton prepared at one labelling can be divided into 3-6 individual doses. Labelling is to be carried out in the activity range of 0.8-1.6 GBq in the way that at the time of application each patient gets the required ^99mTc-activity of 74-185 MBq.

In case of children (see also paragraph “Contraindications”) the activity to be administered is to be determined with Webster’s formula:

A_children (MBq) = [ (N+1) × A_adult (MBq) ] / (N+7),

where N equals to the age of the child, in years.

4.3 Contraindications

RELATIVE CONTRAINDICATIONS
The use of the product is generally contraindicated
– at the age below 18 years,
– in case of pregnant or lactating women,
except when the necessity and importance of obtaining the diagnostic information 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 with the radionuclide.

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.

4.5 Interactions with other medicinal products and other forms of interaction

No interaction has been reported.

4.6 Application during pregnancy and lactation

In general, application of the product during pregnancy and lactation is contraindicated unless the necessity and importance of acquiring the information prevails the risk originating from the radiation exposure.

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. 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. However, should such an event occur as the result of an error or a mistake of the personnel first of all the actually injected activity value of Tc-99m is to be determined. Then the absorbed dose (concerning both the whole body and the individual organs) is to be calculated based on the dosimetry table in paragraph 5.4. The table shows the absorbed dose values in µGy caused by introduction of 1 MBq Tc-99m isotope, which is to be multiplied by the MBq value of the actually injected activity so that the required absorbed dose is obtained. Whether the patient should undergo a treatment and/or an administrative radiation safety procedure is to be decided according to the calculated values.

If administered as prescribed minimum 2.5 mg, maximum 5.0 mg of ^99mTc-phytate is introduced to the body. Pursuant to intravenous acute toxicity experiments on rats no clinical symptoms can be observed up to 4 mg/kg body. In case as the result of an error or a mistake of the personnel the whole content of one vial is injected, it represents 15 mg. It equals to 0.21 mg/kg - calculated with an average body weight of 70 kg -, which is only 5.25% of the mentioned symptom free limit.

Consequently, no toxic effect is expectable in overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V09D B 07

After administered intravenously Tc-99m-phytate forms a microdisperse system (colloid) with calcium ions of the blood. The cells of the liver and the spleen, the Kupffer-cells and the reticuloendothelial system extract that system from the blood (phagocytosis) and 90-95% of the activity appears in the liver. Further 5-10% is deposited in the spleen and the bone marrow. The colloid leaves the liver in the way of slow degradation and hydrolysation of the micro-particles.

Incase of impaired liver function the bone marrow radioactivity is increased and part of the activity appears in the lungs. However, diffuse liver diseases result in an increased spleen activity.

5.2 Pharmacokinetic properties

Tc-99m-phytate introduced intravenously leaves the bloodstream in two parallel processes described with exponential curves:
– Fast process T_1/2 = 2.4-7 min
– Slow process T_1/2 = 69-105 min
The fast process is the result of the operation of the reticulo-endothelial system.

The liver uptake is quick, it can be observed even some minutes after administration. Thirty minutes thereafter 90% of the radioactivity collects in the liver. In contrast, excretion from the liver is extremely slow.

5.3 Preclinical safety data

Pursuant to intravenous acute toxicity experiments on rats no clinical symptoms can be observed up to 4 mg/kg body. If administered as prescribed minimum 2.5 mg, maximum 5.0 mg of ^99mTc-FYTON is introduced to the body. Calculated with an average body weight of 70 kg it equals to 0.9% and 1.8% of the mentioned symptom free limit respectively.

Consequently, application of the product is safe.

Further advantage of the product is that the activity of the applied Tc-99m-pertechnate (in the range of 0.8-1.6 GBq) has no effect on the quantity of the radiochemical impurities, i.e. their total quantity remains below 10% permitted. Therefore, application of the medical product can be considered safe from the point of view of labelling.

5.4 Radiophysical properties of the radionuclide and the absorbed dose values

A single dose of a patient contains 74-185 MBq activity. In case of 70 kg average weight 1 MBq of the injection induces the following absorbed dose in the listed organs:

6. PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

6.2 Incompatibilities

Tin (II) chloride of reducing capability is present in the ampoules of Fyton in vivo kit. (It reduces free pertechnetate of +7 oxidation degree into technetium of +5 oxidation degree, which readily forms a complex entity with the ligand.) Therefore, the content of the ampoules is incompatible with oxidising media (oxidising agents, oxygen of the air, etc.) and moisture. Alkaline media also supports the oxidation of tin (II) before conducting the labelling process. Therefore, incompatibility exists with any chemical bases.

Consequently, the cap and the plug of the ampoules can only be removed right before the radioactive labelling, which should be carried out strictly according to the instructions for use of the product (as detailed in chapter 6.6).

No interaction with other pharmaceuticals has been reported.

6.3 Shelf life

Shelf life of Fyton in vivo kit (lyophilised non-radioactive components in glass ampoules closed with a rubber plug and an aluminium cap) is 12 months from the day of production.

One paper box contains 6 ampoules. Radioactive labelling of the content of the individual ampoules can be done at different occasions within the expiry date (12 months) shown on the label of the ampoule and the paper box.

Tc-99m-Fyton (Fyton labelled with radioactive Tc-99m radionuclide) injection must be used within 3 hours from labelling.

6.4 Special precautions for storage

Fyton in vivo kit is to be stored at room temperature (15-25°C) in its original packaging.

Tc-99m-Fyton injection is to be stored at room temperature (15-25°C) in accordance with the regulations on radioactive materials.

6.5 Nature and composition of the packaging

Fyton in vivo kit contains the components shown in paragraph 2.a and 6.1 as sterile, pyrogen-free freeze dried material. Each ampoule (BEKA type vial of 6 ml) is labelled and closed with a rubber plug and an aluminium cap equipped with a removable plastic top.

6 labelled ampoules are placed in a white cardboard box of 150×100×60 mm dimensions. The box is lined with a spacer insert made of the same material as the box, which secures the ampoules safely. One box contains 6 ampoules, enough for 6 labellings (one labelling each).

The cardboard box is fastened with a celluloid shrinking foil. By removing the shrinking foil and lifting up the upper part of the box the ampoules are available.

6.6 Instruction for use and handling

Fyton in vivo kit must not be used directly as an injection, only Tc-99m-phytate (Tc-99m radioisotope labelled Fyton) can be administered. Tc-99m-phytate is a solution containing a radioactive isotope. When preparing and using it both the pharmaceutical regulations and the rules concerning radioactive materials should be kept. Radioactive labelling is to be carried out as follows:

Place the glass vial containing the freeze-dried material in a small lead pot of 3 mm wall thickness. In aseptic conditions the required activity of sterile Tc-99m-pertechnetate (0.8-1.6 GBq) is injected into the vial through the rubber cap with a sterile syringe. Mix up the vial thoroughly and the labelling process takes place. Thereafter, the solution (or its appropriate portion) can be administered intravenously.

Radiochemical purity of Tc-99m-Fyton should be determined with two kinds of Paper Chromatography tests.

Determination of free pertechnetate (^99mTcO₄-) with Paper Chromatography:

Drop 5 µl of Tc-99m-Fyton solution (approximately 1 MBq/µl) on each of three Whatman 31 ET (cat. no.: 3031915) paper strips of 1.5×20 cm size 1.5 cm from the end. With using acetone as eluent let the front run approximately up to 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:

Labelled complex Tc-99m-FYTON and reduced, hydrolysed ^99mTc: 0.0 - 0.3
Free ^99mTcO₄--: 0.8 - 1.0

Examination of formation of the dispersion (colloid) with Ca₂+ ions:

Drop 5 µl of Tc-99m-Fyton solution (approximately 1 MBq/µl) on each of three Whatman 31 ET (cat. no.: 3031915) paper strips of 1.5×20 cm size 1.5 cm from the end. With using 10% CaCl₂ water solution as eluent let the front run approximately up to 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:

Disperse system of ^99mTc-Phytate and Ca₂+ ions: 0.3 - 0.4
Free ^99mTcO₄-: 0.7 - 1.0

Radiochemical purity is calculated with considering the peak areas. Taking the total activity on the stripe as 100% the activity ratio corresponding to the peak of ^99mTc-phytate provides the radiochemical purity data, which must be minimum 90 %.

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

86.337/1977

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Original Marketing Authorisation:    Dec 21^st, 1977

10. DATE OF REVISION OF THE TEXT

February 18^th, 2002