1. NAME OF THE MEDICINAL PRODUCT

DTPA (Diethylene triamine pentaacetate) in vivo kit for preparation of radiopharmaceutical product (Tc-IK-8)

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 DTPA in vivo kit:

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

3. PHARMACEUTICAL FORM

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

This medical product is for DIAGNOSTIC purposes only.

a.) Field of indication: dynamic kidney studies (kidney function), imaging technique

– Kidney perfusion determination
– Camera renography, GFR determination (glomerular filtration rate)
– Total and particular (each kidney separately) kidney function determination
– Localisation of urine flow blockages
– Vesico-renal reflux verification
– Retained urine volume determination

b.) Field of indication: brain blood-circulation studies

– Revealing vascular and neoplastic brain injuries

c.) Field of indication: other blood-circulation studies

– Determination of the blood flow rate coursing through the heart

d.) Field of indication: examination of the gastrointestinal tract with ^99mTc-DTPA labelled food and drinks

– Localisation of blockages in the oesophagus
– Stomach-oesophagus reflux determination
– Examination of the passage process in the stomach

e.) Field of indication: examination of liquor circulation

– Brain liquor circulation examination
– Liquor stream studies in the spinal cord
– Revealing liquor weep

4.2 Posology and mode of administration

(I.) The quantity of Tc-99m-DTPA prepared at one labelling can be divided into 3-6 individual doses. Labelling is to be carried out in the activity range of 0.8-2.4 GBq in the way that at the time of application each patient gets the required ^99mTc-activity depending upon the actual field of indication. Recommended activity values for the different fields of indication:

a.) Kidney function studies: 111 – 185 MBq
b.) Brain blood-circulation studies: 500 – 600 MBq
c.) Other blood-circulation studies: 185 – 370 MBq
d.) Gastro-intestinal studies: 20 – 40 MBq

(II.) For liquor circulation studies: 600 – 1200 MBq ^99mTc-pertechnate in 3.0 ml volume is added to an ampoule of the DTPA kit. After incubation it is diluted to 6.0 ml with 3.0 ml aqua destillata injection. Recommended activity for one patient in case of lumbar administration or cistern puncture:

e.) Liquor circulation studies: 100 – 200 MBq

(III.) 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.

(IV.) Recommended examination method:

Mode of administration in case of dynamic kidney studies, brain and other blood circulation examinations is intravenous, as bolus. Detection (imaging) should start at the time of administration, therefore, the agent is to be administered when the patient is lying under or sitting in front of the camera. Detection time:
 

At gastro-intestinal studies ^99mTc-DTPA is mixed to food (semolina, chicken liver, boiled egg, etc.) or drink and administered orally. Detection time:

Oesophagus motility: 1-120 sec, continuously
Stomach reflux: 10-15 min
Passage from the stomach: 2 hours

Only the above prescribed dilution of ^99mTc-DTPA is allowed to be applied for liquor circulation studies! It is administered either with cistern puncture (to the brain cistern) or in lumbar way (to the spinal marrow). Images are taken 0.5, 1, 3 and 6 hours thereafter.

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 1.5 mg, maximum 3.0 mg of ^99mTc is introduced to the body. Pursuant to intravenous acute toxicity experiments on mice no clinical symptoms can be observed up to 1.6 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 9 mg.

It is worth to mention that DTPA is applied as a treatment agent in cases of heavy metal poisoning. The recommended human dose is 1790 mg (25.6 mg/kg body weight) trisodium-calcium-DTPA per day. In case as the result of an error or a mistake of the personnel the whole content of one vial is injected, it represents only 0.5% of the mentioned daily human dose.

Consequently, no toxic effect is expectable in overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V09C A 01

As is well-known the hydrophilic, polar molecules not or only slightly bound to the blood plasma are filtrated by the glomerules of the kidneys and leave the body with the primary urine. The most specific glomerularly filtrated compounds are inuline and creatinine, which do not bind to the blood plasma. However, no heteroatom can be introduced to these molecules without changing their physiological properties dramatically. Consequently, only C-12, C-14, H-3, O-15 and in case of creatinine N-13 could be used for radioactive labelling, which would not influence the chemical features of those molecules. However, except for C-14 they are positron emitters with a very short (2-20 min) physical half life, therefore extremely quick synthesis and a PET machine would be necessary to use them in imaging kidney studies. Concerning C-14, its beta emission is not suitable for imaging.

⁵¹Cr-EDTA is a fully glomerularly excreted radioactive complex whose physiological properties are almost identical to those of inuline and does not bind to the blood plasma. From physiological point of view it is suitable to carry out dynamic kidney examinations. Unfortunately, the photon yield of ⁵¹Cr is as low as no image can be taken, only the activity of the blood samples are measured. EDTA and DTPA complexes of ^99mTc radioisotope with excellent imaging features can be synthesised and used as an alternative of ⁵¹Cr-EDTA.

However, while there is no binding between ⁵¹Cr-EDTA and the plasma proteins both in case of ^99mTc-EDTA and ^99mTc-DTPA a certain binding is observed (2-10 %), varying individually. This results in a difference between the GFR (glomerular filtration rate) values determined with using these two agents, which can be corrected if the plasma binding ration is determined at each patient.

More than 90% of ^99mTc-DTPA leaves the bloodstream quickly after administered intravenously and goes to the kidneys where it is excreted glomerularly. No binding in the kidneys is observed, 90% of the introduced activity leaves within 24 hours with the urine. The normal way of excretion is: kidneys-ureter-urinary bladder.

It is a general principle that in the course of isotope diagnostic imaging the radioactive tracer should not influence the examined system, i.e. the physiological processes taking place in the human body. There should have no or only a negligible effect upon the glomerular filtration of the kidneys. The medical product meets this requirement since minimum 1.5 mg, maximum 3.0 mg Tc-99m-DTPA is administered, whose pharmaceutical and pharmacodynamic effect cannot be observed.

5.2 Pharmacokinetic properties

Tc-99m-DTPA introduced intravenously leaves the bloodstream in four parallel processes described with exponential curves:

– 58% of the activity T_1/2 = 3.8 min
– 24% of the activity T_1/2 = 15.6 min
– 16% of the activity T_1/2 = 118 min
– 2% of the activity T_1/2 = 13.6 hours

The quickest (3.8 min) process can probably be reasoned by the extremely fast diffusion of ^99mTc-DTPA in the capillaries to the extravascular, extracellular space.

The maximum activity of ^99mTc-DTPA in the kidneys can be observed 3.5-3.8 min after administration. Such in case 4.4% of the total activity is present in each kidney. The glomerular filtration in the kidneys is significantly faster in dogs than in humans, however, the cumulative excretion after 12 hours is similar: approximately 90%.

The excretion from the kidneys is described with a two-compartment exponential curve:

– 69% of the activity T_1/2 = 1.73 hours
– 27% of the activity T_1/2 = 9.2 hours
4% remains in different tissues.

The above pharmacokinetic excretion process facilitates the advantageous application of ^99mTc-DTPA in blood circulation studies. The excretion takes place in several steps and because of the slow mechanisms enough activity remains in the blood to take the pictures during the blood circulation examinations of 1-10 min. Since the agent is fully excreted through the kidneys there is no need to block the thyroid, which should be done inevitably when using ^99mTc-pertechnetate. This applies to gastrointestinal studies as well.

No selective pharmacokinetic effect is observed when administering ^99mTc-DTPA into the liquor. In fact, blending the agent in the liquor and the liquor flow are traced (physical tracing of a streaming system).

5.3 Preclinical safety data

Pursuant to intravenous acute toxicity experiments on mice no clinical symptoms can be observed up to 1.6 mg/kg body. If administered as prescribed minimum 1.5 mg, maximum 3.0 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 9 mg.

It is worth to mention that DTPA is applied as a treatment agent in cases of heavy metal poisoning. The recommended human dose is 1790 mg (25.6 mg/kg body weight) trisodium-calcium-DTPA per day. In case as the result of an error or a mistake of the personnel the whole content of one vial is injected, it represents only 0.5% of the mentioned daily human dose. Consequently, the application of the medical product is to be considered as safe.

Further advantage of the medical product is that the activity of the applied Tc-99m-pertechnate (in the range of 3-6 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 111-185 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 DTPA in vivo kit. (It reduces free pertechnetate into technetium of +4 oxidation degree, which readily forms a complex entity with DTPA 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 DTPA 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 shown on the label of the ampoule and the paper box.

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

6.4 Special precautions for storage

DTPA in vivo kit is to be stored at room temperature in its original packaging.

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

6.5 Nature and composition of the packaging

DTPA 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

DTPA in vivo kit must not be used directly as an injection, only Tc-99m-DTPA (Tc-99m radioisotope labelled DTPA) can be administered. Tc-99m-DTPA 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 (0.8-2.4 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.

Radioactive labelling for lumbar administration or cistern puncture 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 (600-1200 GBq) exactly in 3.0 ml 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. The solution is to be diluted to 6.0 ml with 3.0 ml Aqua dest. Injection. Thereafter, the solution (or its appropriate portion) can be administered.

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-DTPA should be determined with Paper Chromatography and Thin Layer Chromatography tests.

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

Drop 5 µl of Tc-99m-DTPA 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-DTPA and reduced, hydrolysed ^99mTc: 0.0-0.3
Free ^99mTcO4- : 0.8-1.0

Determination of reduced, hydrolysed ^99mTc with Thin Layer Chromatography:

Drop 5 µl of Tc-99m-DTPA solution (approximately 1 MBq/µl) on each of three ITLC-SG (Gelman Sciences, cat. no.: 61886) plate of 1.5×20 cm size 1.5 cm from the end. With using sodium-chloride 0.9% 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:

Reduced, hydrolysed ^99mTc: 0.3-0.4
Labelled complex Tc-99m-DTPA and free ^99mTcO4-: 0.7-1.0

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.

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

80.006/1988

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Original Marketing Authorisation:    Jan 12^th, 1988

10. DATE OF REVISION OF THE TEXT

February 18^th, 2002