3. PHARMACEUTICAL FORM
Pharmaceutical form of EC in vivo kit: Powder for injection.
Pharmaceutical form of Tc-99m-EC: Radioactive, sterile injection.
4. CLINICAL PARTICULARS
4.1
Therapeutic indications
This
medical product is for DIAGNOSTIC purposes only.
Field of indication: isotope diagnostic kidney scintigraphy, dynamic
imaging examinations of the kidneys. Application is especially
recommended in case of the following diseases:
– Pyelonephritis
– Nephrolythiasis - Ureterolythiasis
– Hydronephrosis
– Other parenchima affections
– Polycystic kidney
– Vesico renal reflux
4.2 Posology
and mode of administration
The quantity
of Tc-99m-EC prepared at one labelling can be divided into 3-6
individual doses. In order a patient of average weight (70 kg) can
obtain the required activity of 90-120 MBq at the time of application
the labelling should be carried out with 0.8-1.6 GBq
Tc-99m-pertechnetate activity.
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 mode of examination:
Tc-99m-EC injection is administered to the patient as bolus to the
brachial vein when the patient has already been positioned for taking
the exposure (sits in front of or lies above or below the camera). The
camera should be adjusted to the back of the patient. Series of
exposures are taken:
30 exposures of 1 second each (perfusion phase), then 120 exposures of
20 seconds each (uptake and washout phase). At low washout more
exposures can also be taken. Washout can be fastened by administration
of Furosemid injection, however, it should be considered at the
evaluation of the kinetic curve drawn form the results of the picture
series.
The
total time consumption of the examination is 30 minutes.
4.3
Contraindications
RELATIVE CONTRAINDICATIONS
The use of the product is absolutely contraindicated
– at the age below 18 years,
– in case of pregnant or lactating women,
except when the necessity and importance of the treatment prevails the
risk originating from the radiation exposure.
ABSOLUTE CONTRAINDICATION
Never can the product be applied,
– if the patient does not provide an oral or written consent of being
treated by radionuclide therapy.
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
In case of
patients with hypertonia, if the patient takes ACE inhibitors, the
camera renogram can be different from the normal one even in case of
healthy renal function. This fact should be taken into consideration at
the evaluation of the renograms. (Slower wash-out is usually observed in
case of taking ACE inhibitors).
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 absorbed radiation
dose.
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 0.33 mg, maximum 0.67 mg of
Tc-99m-EC is introduced to the body. Pursuant to intravenous acute
toxicity experiments on mice no clinical symptoms can be observed up to
11.4 mg/kg body. LD50 value of 38.4 mg/kg body was determined in a
14-day experiment. In case as the result of an error or a mistake of the
personnel the whole content of one vial is injected, it represents 2 mg,
which is 0.029 mg/kg body for a patient of average weight (70 kg). This
equals to 0.25% of the symptom-free toxicity level. Consequently, no
toxic effect is expectable in overdose, measures might only be necessary
due to overdose of the radioactivity (see above).
However, dividing the labelled Tc99m-EC solution into fewer parts than
the prescribed minimum patient number (bigger doses) may result in a
saturation effect and may influence the pharmacokinetic properties of
the compound and therefore, the diagnostic value of the medical product.
5. PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
ATC
code: V09C A
Tc-99m-EC has been developed for diagnostic examination of the tubular
kidney function. Besides imaging the product facilitates the
determination of the characteristic parameters of the renogram (Tmax,
T1/2) by the help of the exposure series and the effective
plasma quantity perfusing through the kidneys can also be calculated.
After administered intravenously Tc-99m-EC leaves the blood rapidly
through the kidneys, where it is excreted in the tubular way. The normal
washout route is kidneys – ureters – urinary bladder and this applies to
the cases of deficient kidney functions, too. Consequently, none of the
liver and the spleen is visualised on the pictures.
Pharmacological properties of Tc-99m-EC are similar to those of PAH and
iodohippurane. However, while the plasma binding value of iodohippurane
is 33%, the same is 29% for Tc-99m-EC. It is worth to mention that the
plasma binding of Tc-99m-MAG3, which is also applied in camera
renography and secreted in the tubular way as well) exceeds 80%.
Excellent imaging properties of Tc-99m-EC are accrued from the molecule
structure similar to hippurate, namely the spatial conformation of
oxo-oxygen and two oxygen atoms of the adjacent carboxyl groups, which
is finally reducible to the similarity of the triangle formed by three
oxygen atoms because the enzyme in the tubules of the kidneys recognises
this geometry, it is specific to it, this geometry facilitates the
excretion.
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.
Tc-99m-EC should have no or only a negligible effect upon the excretory
function of the kidneys. The medical product meets this requirement
since minimum 0.33 mg, maximum 0.67 mg Tc-99m-EC is administered, whose
pharmaceutical effect cannot be observed.
5.2
Pharmacokinetic properties
Since
Tc-99m-EC binds to blood plasma much less than Tc-99m-MAG3 (29% and 80%
respectively) its kidney extraction coefficient is a much closer value
to that of o-iodohippurate (0.75 and 0.85 respectively). Therefore,
Tc-99m-EC leaves the bloodstream very rapidly: maximum activity of the
kidneys (Tmax) can be observed 3-3.5 minutes after
administration in normal cases. Biological half life is T1/2
< 11 minutes when the kidney function is intact. During 20-25 minutes of
the dynamic kidney study 75-80% of Tc-99m-EC is excreted with urine.
Impaired kidney function increases both Tmax and T1/2
significantly. However, it is to be noticed that not even a tiny
fraction of Tc-99m-EC remains in the bloodstream or passes out through
another way, consequently, the liver does not appear on the picture even
in case of impaired kidney function. The kidney image is of the best
resolution, the parenchima is well confinable and the calyx is clearly
visible within the kidney.
Studying the kidney-clearance of Tc-99m-EC in comparison with that of
I-125-hippurane the following values are obtained:
CL(I-125- hippurane): 604 ml/min
CL(Tc-99m-EC): 420 ml/min
5.3
Preclinical safety data
Pursuant to intravenous acute toxicity experiments on mice no clinical
symptoms can be observed up to 11.4 mg/kg body. LD50 value of 38.4 mg/kg
body was determined in a 14-day experiment. In case as the result of an
error or a mistake of the personnel the whole content of one vial is
injected it represents 2 mg, which is 0.029 mg/kg body for a patient of
average weight (70 kg). This equals to 0.25% of the symptom-free
toxicity level. Nevertheless, if administered as prescribed minimum 0.33
mg, maximum 0.67 mg of Tc-99m-EC is introduced to the body because one
vial represents 3-6 patients’ dose. Accordingly, application of the
medical product can be considered as safe.
It is an advantage that the shelf life of Tc-99m-EC (3 hours from
labelling) and the time consumption of one examination (20-25 minutes)
enable the completion of the camera renography examination of 6 patients
comfortably with Tc-99m-EC obtained from one labelling.
Further benefit of the medical product is that the activity of the
applied Tc-99m-pertechnetate has no effect on the radiochemical purity
of the medical product. Whether the activity of Tc-99m-EC falls in the
usually applied range of 0.8-1.6 GBq or in the extreme 37 MBq – 10 GBq
range the total quantity of the radiochemical impurities 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
No
interaction with other pharmaceuticals has been reported.
Excipients freeze dried together with the active ingredient in ampoule
“A” ensure a basic medium so that radioactive labelling can take place
at pH = 12. Therefore, the content of ampoule “A” is incompatible with
any acids. Furthermore, the active ingredient bears sulphydryl groups,
which are sensitive to acids and moisture. The cap of ampoule “A” can
thence be opened right before the radioactive labelling only, which
should be then performed within the time frame (and in the way)
described in the instructions of use and handling of the medical
product.
The effective agent in ampoule “B” is tin (II) chloride with reducing
capability. (It reduces free pertechnetate into technetium of +5
oxidation degree, which is able to form a complex entity with EC
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. The cap of ampoule “B” can thence be opened right
before the radioactive labelling only, which should be then performed
within the time frame (and in the way) described in the instructions of
use and handling of the medical product.
Ampoule “C” only contains buffers, whose function is to neutralise the
alkaline solution of Tc-99m-EC after labelling so that it can be
administered intravenously. Therefore, incompatibility exists with any
chemical bases. The cap of ampoule “C” can be opened right before the
radioactive labelling only, which should be then performed within the
time frame (and in the way) described in the instructions of use and
handling of the medical product.
6.3
Shelf life
Shelf
life of EC 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 ampoules for 4 labellings (4 pcs of “A”, 4 pcs of
“B” and 4 pcs of “C” ampoules). Four radioactive labellings can be
carried out at different occasions within the expiry date shown on the
label of the ampoules and the paper box.
Tc-99m-EC (EC labelled with radioactive Tc-99m radionuclide) injection
must be used within 3 hours from labelling.
6.4
Special precautions for storage
EC
in vivo kit is to be stored in a refrigerator (2-8 °C) in its
original packaging.
Tc-99m-EC injection is to be stored at room temperature (15-25 °C) in
accordance with the national regulations on radioactive materials.
6.5
Nature and composition of the packaging
EC
in vivo kit contains the components in ampoules “A”, “B” and “C”
shown in paragraph 2.a and 6.1 in ampoules “A”, “B” and “C” as sterile,
pyrogen-free freeze dried material. Each ampoule (so called “BEKA” glass
vial of 6 ml) is labelled and closed with a rubber plug and an aluminium
cap equipped with a removable plastic top. Strips of different colours
on the label of the ampoules facilitates the identification: Ampoule “A”
bears a label with a red strip, while “B” is yellow and “C” is green.
The 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
4 sets of 3 ampoules “A”, “B” and “C”, enough for 4 labellings (one
labelling each set).
The cardboard box is fastened with 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
EC
in vivo kit and its components must not be used directly, only
Tc-99m-EC (Tc-99m radioisotope labelled EC) can be administered.
Tc-99m-EC 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:
One box contains 4 sets of 3 ampoules “A”, “B” and “C”, enough for 4
labellings. For one labelling: place an ampoule “A” in a small lead pot
of 3 mm wall thickness. In aseptic conditions 2.0 cm3 of sterile
Tc-99m-pertechnetate (0.8-1.6 GBq) is injected into the vial through the
rubber cap with a sterile single-use syringe. Shake the vial vigorously.
Dissolve the content of ampoule “B” in 2.0 cm3 0.9% sterile
sodium-chloride solution and after complete dissolution immediately
inject 0.5 cm3 of it to ampoule “A”. Let ampoule “A” stand
for 15 minutes at room temperature (15-25 °C) but meanwhile, shake it a
couple of time.
Dissolve the content of ampoule “C” in 1.0 cm3 0.9% sterile
sodium-chloride solution and after complete dissolution inject the
entire volume to ampoule “A”. Shake well again.
Now, Tc-99m-EC obtained can be administered intravenously. 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-EC should be examined with Thin Layer Chromatography.
Determination of free pertechnetate (99mTcO4-)
and reduced, hydrolysed 99mTc with Thin Layer Chromatography
in one step:
Drop 5
µl of Tc-99m-EC solution on each of three Kieselgel 60 (F254) (Merck
cat. no.: 5554) plate of 1.5×20 cm size at 1.5 cm from the end. With
using 96% Ethanol 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:
