NAME OF THE MEDICINAL PRODUCT

Techida (N-(2,6-diethyl-phenyl)-carbamoylmethyl-imino-diacetic acid) in vivo kit for preparation of radiopharmaceutical product (Tc-IK-6)

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.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Composition of Techida in vivo kit (powder ampoule):

Composition of Tc-99m-Techida radioactive injection:

PHARMACEUTICAL FORM

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

CLINICAL PARTICULARS

Therapeutic indications

This medical product is for DIAGNOSTIC purposes only.

Field of indication: radioisotopic examination of the hepatobiliary system
– Dynamic examination of the function of the hepatocytes.
– Evaluation of the transplanted liver.
– Dynamic examination of flow disorders in the hepatobiliary system (blockage in the biliary duct, etc.).
– Examination of the acute cholecystitis
– Verification of focalis nodular hyperplasia

Posology and mode of administration

The quantity of Tc-99m-Techida 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 150-200 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.

Recommended examination method:

a.) When examining liver cells imaging starts simultaneously with intravenous administration. The perfusion, uptake and excretion phases are determined based on the picture series. The curve generated from the picture series is evaluated quantitatively.

b.) When examining the hepatobiliary system time-activity curves are determined with the ROI-method based on the exposures 2, 5, 10, 15, 30 and 45 minutes after intravenous administration. Recommended ROIs: heart, right lobe of the liver, gallbladder, duodenum.

Approximate data on the visibility of certain organs in normal cases:

In case of impaired liver function the kidney shadow is visible for longer.

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.

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.

Interactions with other medicinal products and other forms of interaction

No interaction has been reported.

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 diagnostic information prevails the risk originating from the radiation exposure.

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.

Undesirable effects

Occurrence of undesirable effects and symptoms is unexpected.

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 5 mg, maximum 10 mg of ^99mTc-Techida is introduced to the body. Pursuant to intravenous acute toxicity experiments on mice no clinical symptoms can be observed up to 9 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 30 mg. It equals to 0.43 mg/kg - calculated with an average body weight of 70 kg -, which is only 4.8% of the mentioned symptom free limit.

Consequently, no toxic effect is expectable in overdose.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

ATC code: V09D A 02

After administered intravenously ^99mTc-Techida binds to plasma proteins and is transported to the liver in that form. Similarly to bilirubin, it is taken up by the liver cells in an anionic active transport process. Uptake highly depends upon the liver function: In case of high bilirubin level the liver is unable to excrete ^99mTc-Techida, which leaves the body mostly through the kidneys such in case. If so, the kidneys and later the urinary bladder are intensively visible in the gamma-camera pictures.

The following three factors predominantly govern the excretion of ^99mTc-Techida by the liver:
– Plasma albumin concentration
– Intensity of the blood flow through the liver
– Hepatocyte function
^99mTc-Techida is excreted either in intact form or bound to bile acids. The normal way of elimination is: liver – gallbladder – duodenum – intestines.

Pharmacokinetic properties

Tc-99m-Techida quickly leaves the blood: 1 hour after administration less than 1% of the activity remains in the bloodstream.

^99mTc-Techida appears in the liver during the first minute after being injected but the maximum activity is observed after 10-15 minutes. Excretion from the liver is characterised by T_1/2= 20-25 minutes half life. It is strongly influenced by the plasma albumin concentration, the intensity of blood circulation and the hepatocyte function.

15 minutes after administration the bile duct is visible in the picture and after 30 minutes the gallbladder can be clearly imaged as well. The maximum activity in the latter appears 30-40 minutes thereafter.

In normal cases the duodenum is observed in the exposures 40-45 minutes after injection.

Preclinical safety data

Pursuant to intravenous acute toxicity experiments on mice no clinical symptoms can be observed up to 9 mg/kg body. If administered as prescribed minimum 5 mg, maximum 10 mg of ^99mTc is introduced to the 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 30 mg. It equals to 0.43 mg/kg - calculated with an average body weight of 70 kg -, which is only 4.8% of the mentioned symptom free limit.

Consequently, application of the product is safe.

Further advantage of the medical 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.

Radiophysical properties of the radionuclide and the absorbed dose values

A single dose of a patient contains 150-200 MBq activity. In case of 70 kg average weight 1 MBq of the injection induces the following absorbed dose in the listed organs:

PHARMACEUTICAL PARTICULARS

List of Excipients

Incompatibilities

Tin (II) chloride of reducing capability is present in the ampoules of Techida in vivo kit. (It reduces free pertechnetate into technetium of +4 oxidation degree, which readily forms a complex entity with Techida 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.

Shelf life

Shelf life of Techida in vivo kit (lyophilised non-radioactive components in glass ampoules closed with a rubber plug and an aluminium cap) is 6 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 (6 months) shown on the label of the ampoule and the paper box.

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

Special precautions for storage

Techida in vivo kit is to be stored in a refrigerator at 2-8°C in its original packaging.

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

Nature and composition of the packaging

Techida 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.

Instruction for use and handling

Techida in vivo kit must not be used directly as an injection, only Tc-99m-Techida (Tc-99m radioisotope labelled Techida) can be administered. Tc-99m-Techida 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 let it stand for 15 minutes at room temperature (15-25 °C), while the labelling process takes place. Thereafter, the solution (or its appropriate portion) can be administered intravenously.

pH value of the labelled product is 5.0-8.0. It should be used within 3 hours from labelling. Within this period the quantity of the radiochemical impurities should not exceed 10%.

Radiochemical purity of Tc-99m-Techida should be determined with Paper Chromatography and Thin Layer Chromatography tests.

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

Drop 5 µl of Tc-99m-Techida solution (approximately 1 MBq/µl) on each of three Polygram-SYL-NHR (Mocherey-Nogel) plate of 1.5×20 cm size 1.5 cm from the end. With using 12% sodium chloride 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:

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

Determination of reduced, hydrolysed ^99mTc with Paper Chromatography:

Drop 5 µl of Tc-99m-Techida solution (approximately 1 MBq/µl) on each of three Whatman 1 Chr paper strip of 1.5×20 cm size 1.5 cm from the end. With using the mixture of water and ethylene glycol (10:90) 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:

Reduced, hydrolysed ^99mTc: 0.0-0.2
Labelled complex Tc-99m-Techida and free ^99mTcO₄- : 0.8-1.0

Radiochemical purity (H) is calculated with the following formula:

where H is the radiochemical purity in %, A’_PC is the area of the peak of the impurity (free pertechnetate) and A_PC is the total area of all peaks from the paper chromatography test. A’_TLC is the area of the peak of the impurity (reduced, hydrolysed ^99mTc) and A_TLC is the total area of all peaks from the thin layer chromatography test.

The radiochemical purity should be minimum 90% at expiry.

MARKETING AUTHORISATION HOLDER

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

NUMBER OF THE MARKETING AUTHORISATION

80.649/1985

DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Original Marketing Authorisation:    Mar 19^th, 1985

DATE OF REVISION OF THE TEXT

February 14^th, 2002