1. NAME OF THE MEDICINAL PRODUCT

Pyron (sodium pyrophosphate) in vivo kit for preparation of radiopharmaceutical product (Tc-IK-5)

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 Pyron in vivo kit:

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

3. PHARMACEUTICAL FORM

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

This medical product is for DIAGNOSTIC purposes only.

Field of indication:

a.) Bone scintigraphy, especially recommended in the following cases:
– Primer bone tumors
– Bone metastases of other tumors (e.g. prostate, breast, lung cancers)
– Osteomyelitis
– Metabolic bone diseases
– Paget’s disease
b.) Visualisation of acute myocardial infarction
c.) Blood pool scintigraphy
d.) Spleen scintigraphy examinations

4.2 Posology and mode of administration

(I.) For bone scintigraphy studies and visualisation of acute myocardial infarction Tc-99m-pyrophosphate is used directly. The quantity prepared at one labelling can be divided into 3-6 individual doses. Labelling is to be carried out in the activity range of 1.3-3.0 GBq in the way that at the time of application each patient gets the required ^99mTc-activity of 300-500 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 time of taking bone scintigraphy exposures: 3-4 hours after administration.
Recommended time of imaging acute myocardialis infarctus: 30-60 minutes after administration.

(II.) In case of blood pool scintigraphy red blood cells are pretreated as follows: The content of a Pyron ampoule is dissolved in 2-5 ml sterile 0.9% sodium-chloride solution, it is divided into one or two doses and a dose is injected intravenously. After 15-30 minutes 300-400 MBq ^99mTc-pertechnate (generator eluate) is administered intravenously, which localises in the red blood cells and labels them.

Recommended time of taking blood pool scintigraphy exposures: 15 minutes after administration.

(III.) At spleen scintigraphy red blood cells are pretreated in vivo as follows: The content of a Pyron ampoule is dissolved in 2-5 ml sterile 0.9% sodium chloride solution, it is divided into 3-6 doses and a dose is injected intravenously. After 15-30 minutes 10 ml blood is taken from each patient into a tube containing anti-coagulant (heparin or sodium citrate, etc.). The red blood cell suspension is separated by centrifugation and 75-100 MBq ^99mTc-pertechnate (generator eluate) of equal volume is added. After homogenising the red blood cells are treated with heat at 49.5°C for 20 minutes (destruction). After cooling the labelled, destructed red blood cells are re-injected to the patient intravenously, they will be collected in the spleen.

Recommended time of taking spleen scintigraphy exposures: 30-60 minutes after re-injecting.

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 4.17 mg, maximum 12.5 mg of ^99mTc-pyrophosphate is introduced to the body. Pursuant to intravenous acute toxicity experiments on rats no clinical symptoms can be observed up to 5 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 25 mg. It equals to 0.36 mg/kg - calculated with an average body weight of 70 kg -, which is only 7.1% of the mentioned symptom free limit.

Consequently, no toxic effect is expectable in overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V09B A 03

After administered intravenously the labelled Tc-99m-pyrophosphate — similarly to Tc-99m-diphosphonates (e.g. methylene-diphosphonate, 1-hydroxy-ethylidene-1,1-diphosphonate) — leaves the blood and concentrates mainly in the skeleton but it visibly appears in the liver as well. The mechanism of the bone uptake is ion exchange and chemisorption in the inorganic matrix of the bone: hydroxy-apatite [ Ca₁₀(PO₄)₆(OH)₂ ], which is of ionic nature. Phosphate groups on the surface of the bone matrix take part in an ion exchange reaction with the free –PO₃Na₂ groups of pyrophosphate co-ordinated to technetium. This way radioactive Tc-99m binds on the bone matrix. This process is accomplished with normal bone as well but binding is significantly more extensive where
– the blood supply of the bone is increased,
– the bone formation activity (osteoblast function) is increased.

Therefore, on the location of bone lesions (primer tumors, metastases, splittings and fractions of the bone, inflamed bone) intensive radioactivity is observed, which enables imaging.

A similar uptake mechanism is presumable in case of acute myocardial infarction: Calcium and phosphate build in the necrotic tissues, which offers the possibility of chemisorption of ^99mTc-pyrophosphate. Since the calcium and phosphate infiltration is only intensive in case of fresh infarcts (not older than 72 hours) imaging provides a positive response such in cases exclusively. To have an appraisable image the mass of the infarct should exceed 5 grams.

The reason of the appearance in the liver is that the enzymes of the liver split the P-O-P bonds in ^99mTc-pyrophosphate and the complex compound transforms into reduced-hydrolysed technetium, which localises in the liver.

Approximately 45% of the intravenously administered ^99mTc-pyrophosphate appears in the bone in the 4^th hour after injection while 20% in the liver and 18% in the urine at the same time. Approximately 2% remains in the bloodstream, its 40% is bound to the red blood cells and 60% is in the plasma.

However, tin(II)-pyrophosphate solution made of the content of Pyron powder ampoule with physiological saline has different pharmacology features. Amongst in vitro circumstances tin(II)-pyrophosphate forms an adduct with red blood cells separated from the blood and the same adduct is generated when tin(II)-pyrophosphate is introduced intravenously. Thereafter, more than 90% of ^99mTc-pertechnate injected intravenously localises in the red blood cells because ^99mTc-pyrophasphate complex forms in the red blood cell – tin(II)-pyrophosphate adduct in vivo as well.

If the red blood cell – tin(II)-pyrophosphate adduct is centrifuged from the tin(II)-pyrophosphate treated blood it can be labelled with ^99mTc-pertechnate in vitro as well. After destruction with heat and re-injecting to the vessels the destructed and labelled red blood cells are collected in the spleen.

5.2 Pharmacokinetic properties

50% of Tc-99m-Pyron introduced intravenously leaves the bloodstream in 38 minutes, 83% in 4 hours. Meanwhile, 45% of the activity appears in the bones, 20% in the liver and 18% is excreted through the kidneys.

In case of fresh myocardial infarct (<72 h) ^99mTc-pyrophosphate localise in 30-60 minutes in the necrotic tissues, according to their extensity and mass.

Intravenously administered tin(II)-pyrophosphate not labelled with radioisotope collects in the red blood cells in 10-15 minutes. 96% of ^99mTc-pertechnate injected thereafter appears in the red blood cells and remains bound to them after 1 hour, too.

Red blood cells destructed and labelled in vitro are present in the spleen 30 minutes after re-injected almost exclusively.

5.3 Preclinical safety data

Pursuant to intravenous acute toxicity experiments on mice no clinical symptoms can be observed up to 5 mg/kg body. If administered as prescribed minimum 4.17 mg, maximum 12.5 mg of ^99mTc-Pyrophosphate 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 25 mg. It equals to 0.36 mg/kg — calculated with an average body weight of 70 kg —, which is only 7.1% of the mentioned symptom free limit.

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 1.3-3.0 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 300-500 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 Pyron in vivo kit. (It reduces free pertechnetate into technetium of +4 oxidation degree, which readily forms a complex entity with Pyron 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 Pyron 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-Pyron (Pyron labelled with radioactive Tc-99m radionuclide) injection must be used within 3 hours from labelling.

6.4 Special precautions for storage

Pyron in vivo kit is to be stored at room temperature in its original packaging protected from light and oxidising agents.

Tc-99m-pyrophosphate 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

Pyron 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

Pyron in vivo kit can be used in two different ways:

In case of bone scintigraphy and myocardial infarct examinations the content of the Pyron in vivo kit must not be used directly as an injection, only Tc-99m-Pyron (Tc-99m radioisotope labelled Pyron) can be administered. Tc-99m-Pyron 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 (1.3-3.0 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 - 7.0. It should be used within 3 hours from labelling. Within this period the quantity of the radiochemical impurities should not exceed 10%.

When carrying out blood pool scintigraphy and spleen scintigraphy examinations the content of the Pyron ampoule is dissolved in physiological saline and the solution is administered to the patients directly. Then:

In case of blood pool scintigraphy the red blood cells are pretreated as follows: The content of a Pyron ampoule is dissolved in 2-5 ml sterile 0.9% sodium-chloride solution, the solution is divided into one or two doses and a dose is injected intravenously. After 15-30 minutes 300-400 MBq 99mTc-pertechnate (generator eluate) is administered intravenously, which localises in the red blood cells and labels them.

At spleen scintigraphy first the red blood cells are pretreated in vivo as follows: The content of a Pyron ampoule is dissolved in 2-5 ml sterile 0.9% sodium chloride solution, it is divided into 3-6 doses and a dose is injected intravenously. After 15-30 minutes 10 ml blood is taken from each patient into a tube containing anti-coagulant (heparin or sodium citrate, etc.). The red blood cell suspension is separated by centrifugation and 75-100 MBq ^99mTc-pertechnate (generator eluate) of equal volume is added. After homogenising the red blood cells are treated with heat at 49.5°C for 20 minutes (destruction). After cooling the labelled, destructed red blood cells are re-injected to the patient intravenously, they will be collected in the spleen.

Radiochemical purity of Tc-99m-Pyron 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-Pyron 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 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-Pyron 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-Pyron 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

80.217/1982

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Original Marketing Authorisation:    Jan 22^nd, 1982

10. DATE OF REVISION OF THE TEXT

February 18^th, 2002