3. PHARMACEUTICAL FORM
Pharmaceutical form of Glukon in vivo kit: Powder for injection
Pharmaceutical form of Tc-99m-gluconate: Radioactive, sterile injection
4. CLINICAL PARTICULARS
4.1
Therapeutic indications
This medical
product is for DIAGNOSTIC purposes only.
Field of
indication: In vitro labelling of red blood cells to be re-injected for
a.) Blood pool scintigraphy,
b.) Spleen scintigraphy examinations
4.2 Posology
and mode of administration
In vitro
pretreatment of red blood cells with Glukon for labelling with
99mTc-pertechnate:
The content of a Glukon ampoule is dissolved in 5 ml sterile 0.9%
sodium-chloride solution, it is divided into 3-6 doses and a dose is
used to label the red blood cells of one patient in vitro. 10
ml blood is taken from each patient into a tube containing
anti-coagulant (e.g.: ACD, etc.). The red blood cell suspension is
separated by centrifugation and 5 ml sterile 0.9% sodium-chloride
solution is added. Homogenise the suspension carefully and incubate at
room temperature for 05 minutes. Again, the red blood cell suspension is
separated by centrifugation and washed with 5 ml sterile 0.9%
sodium-chloride solution.
In vitro labelling of red blood cells for blood pool
scintigraphy:
300-400 MBq 99mTc-pertechnate is added to the
Glukon-pretreated red blood cells of each patient, the suspension is
mixed carefully and incubated at room temperature for 15 minutes. The
red blood cells are separated by centrifugation and washed with 5 ml
sterile 0.9% sodium-chloride solution. The suspension is completed with
sterile 0.9% sodium-chloride solution to the original volume of the
blood sample (10 ml). Labelling efficiency is minimum 80%. After
homogenisation the red blood cells are ready to be re-injected to the
patient.
Recommended time of taking blood pool scintigraphy exposures: 15 minutes
after administration.
In vitro labelling of red blood cells for spleen scintigraphy:
74-100 MBq 99mTc-pertechnate is added to the
Glukon-pretreated red blood cells of each patient, the suspension is
mixed carefully and incubated at room temperature for 15 minutes. The
red blood cells are separated by centrifugation and washed with 5 ml
sterile 0.9% sodium-chloride solution. The suspension is completed with
sterile 0.9% sodium-chloride solution to the original volume of the
blood sample (10 ml). After homogenisation the red blood cells are
incubated at 49.5°C for 20 minutes (degradation). After cooling to room
temperature the red blood cells are to be re-injected to the patient.
They are collected in the spleen.
Recommended time of taking spleen scintigraphy exposures: 30-60 minutes
after re-injecting.
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.
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 16 mg, maximum 32 mg of 99mTc-gluconate
is introduced to the body. Pursuant to intravenous acute toxicity
experiments on rats no clinical symptoms can be observed up to 800 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 100 mg. It
equals to 1.43 mg/kg - calculated with an average body weight of 70 kg
-, which is only 0.18% of the mentioned symptom free limit.
Consequently, no toxic effect is expectable in overdose.
5. PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
ATC
code: V09C A 05
After administered intravenously 50-70% of Tc-99m-gluconate binds to the
plasma proteins of the blood and is slowly excreted through the kidneys
both via glomerular and tubular secretion. Approximately 25% of the
activity remains in the tubules for a longer time.
Tin(II)-gluconate of the solution made of the content of the Glukon
ampoule with physiology saline solution infiltrates into the red blood
cells in vitro, and absorbs the activity added later because of
the formation of the 99mTc-gluconate – red blood cell
complex. After re-injected the labelled red blood cells remain in the
circulation and facilitate the examination of the stationer and
non-stationer phases of the circulation.
5.2 Pharmacokinetic properties
Tc-99m-gluconate introduced intravenously leaves the bloodstream slowly
and goes to the kidneys. The maximum activity is observed there 1-2
hours after administration. The excretion is slow: 70% of the introduced
activity appears in the urine after 24 hours.
99mTc-labelled red blood cells prepared in vitro
with using the Glukon kit remain in the circulation within an hour after
re-injecting, the slow excretion begins thereafter only. Labelled but
heat-degraded and re-injected red blood cells are present in the spleen
30 minutes after re-injected almost exclusively. Their excretion is
slow, too.
5.3
Preclinical safety data
Pursuant to intravenous acute toxicity experiments on mice no clinical
symptoms can be observed up to 800 mg/kg body. If administered as
prescribed minimum 16 mg, maximum 32 mg of 99mTc-Gluconate is
introduced to the body. Calculated with an average body weight of 70 kg
it equals to 0.03 and 0.06% 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 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 Glukon
in vivo kit. (It reduces free pertechnetate 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
Glukon 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-Glukon (Glukon labelled with radioactive Tc-99m radionuclide)
injection must be used within 3 hours from labelling.
6.4 Special
precautions for storage
Glukon
in vivo kit is to be stored at room temperature in its original
packaging protected from oxidising agents.
Tc-99m-gluconate 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
Glukon 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
In
vitro pretreatment of red blood cells with Glukon for labelling
with 99mTc-pertechnate:
The content of a Glukon ampoule is dissolved in 5 ml sterile 0.9%
sodium-chloride solution, it is divided into 3-6 doses and a dose is
used to label the red blood cells of one patient in vitro. 10
ml blood is taken from each patient into a tube containing
anti-coagulant (e.g.: ACD, etc.). The red blood cell suspension is
separated by centrifugation and 5 ml sterile 0.9% sodium-chloride
solution is added. Homogenise the suspension carefully and incubate at
room temperature for 05 minutes. Again, the red blood cell suspension is
separated by centrifugation and washed with 5 ml sterile 0.9%
sodium-chloride solution.
In vitro labelling of red blood cells for blood pool
scintigraphy:
300-400 MBq 99mTc-pertechnate is added to the
Glukon-pretreated red blood cells of each patient, the suspension is
mixed carefully and incubated at room temperature for 15 minutes. The
red blood cells are separated by centrifugation and washed with 5 ml
sterile 0.9% sodium-chloride solution. The suspension is completed with
sterile 0.9% sodium-chloride solution to the original volume of the
blood sample (10 ml). Labelling efficiency is minimum 80%. After
homogenisation the red blood cells are ready to be re-injected to the
patient.
Recommended time of taking blood pool scintigraphy exposures: 15 minutes
after administration.
In vitro labelling of red blood cells for spleen scintigraphy:
74-100 MBq 99mTc-pertechnate is added to the
Glukon-pretreated red blood cells of each patient, the suspension is
mixed carefully and incubated at room temperature for 15 minutes. The
red blood cells are separated by centrifugation and washed with 5 ml
sterile 0.9% sodium chloride solution. The suspension is completed with
sterile 0.9% sodium chloride solution to the original volume of the
blood sample (10 ml). After homogenisation the red blood cells are
incubated at 49.5°C for 20 minutes (degradation). After cooling to room
temperature the red blood cells are to be re-injected to the patient.
They are collected in the spleen.
Recommended time of taking spleen scintigraphy exposures: 30-60 minutes
after re-injecting.
Radiochemical purity of Tc-99m-Glukon 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-gluconate 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-Glukon 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-Glukon and free 99mTcO4- :
0.7-1.0
Radiochemical purity (H) is calculated with the following formula:
