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:
Achildren (MBq) = [ (N+1) × Aadult (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 4th 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
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:
