3. PHARMACEUTICAL FORM
Pharmaceutical
form of DMSA in vivo kit:
Powder for injection
Pharmaceutical form of Tc-99m-DMSA:
Radioactive, sterile injection
4. CLINICAL PARTICULARS
4.1
Therapeutic indications
This
medical product is for DIAGNOSTIC purposes only.
Fields of indication:
- Kidney scintigraphy, static kidney imaging, localisation of the
kidneys
- Determination of the functional mass of the kidney
- Determination of the relative function ratio (percentage) of the left
and right kidneys
4.2 Posology and mode of administration
(I.) The quantity of Tc-99m-DMSA prepared at one
labelling can be divided into 3-6 individual doses. Labelling is to be
carried out in the activity range of 1.0-1.8 GBq in the way that at the
time of application each patient gets the required 99mTc-activity
of 111 – 185 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 examination method:
Mode of
administration is intravenous injection. Detection (imaging) is
recommended to start 1-3 hours after administration. In case of
functional studies (if required) the time function of accumulation after
administration can also be measured.
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 0.25 mg, maximum 0.5 mg of
99mTc-DMSA is introduced to the body. Pursuant to intravenous
acute toxicity experiments on mice no clinical symptoms can be observed
up to 0.43 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
1.5 mg, which equals to 0.0214 mg/kg body (for 70 kg average body
weight). This only 5% of the symptom-free limit.
Consequently, no toxic effect is expectable in overdose.
5. PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
ATC
code: V09C A 02
The structure of DMSA-complex administered to the body is [99mTc-(DMSA)2],
i.e. it is a biscomplex. Its 75% binds to the plasma proteins of the
blood. Binding highly depends upon which pH value was ensured by the
buffer of the kit. Optimum pH is in the range of 3-4.
[99mTc-(DMSA)2] is taken up by the kidneys in form
bound to the plasma proteins. One of the ligands is replaced by an –SH
group of the receptor in the tubules (especially in the proximal ones),
a [99mTc-(DMSA)-receptor] complex is formed, one DMSA
molecule gets free and is excreted with the urine. This mechanism
results in binding of 0.1 mg DMSA per kg body.
Since the proximal tubules are situated in the cortex of the kidneys,
imaging is formed by visualising the cortex itself. 40-50% of the
injected activity appears in the kidney cortex and approximately 3% in
the liver. In case of patient with impaired kidney function this ratio
decreases and the radioactivity of the liver increases significantly.
Finally, 99mTc-(DMSA) bound in the kidneys is excreted with
the urine.
5.2 Pharmacokinetic properties
Tc-99m-DMSA introduced intravenously leaves the bloodstream in three
parallel processes described with exponential curves, the effective half
life is approximately 1 hour. Most of the activity leaves the
bloodstream during the first two phases (T1/2 = 40 min and
120 min).
1 hour after administration 25-35% of the 99mTc-DMSA activity
is localised in the kidneys, while after 3 hours 40-50%. Simultaneously,
25% of the administered activity is excreted with the urine during the
first hour. After 6 hours the excretion increases.
5.3 Preclinical safety data
Pursuant to intravenous acute toxicity experiments on mice no clinical
symptoms can be observed up to 0.43 mg/kg body. If administered as
prescribed minimum 0.25 mg, maximum 0.5 mg of 99mTc is
introduced to the body. In case of average weight (70 kg) they represent
0.8% and 1.6% of the symptom free limit, respectively.
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 1.0-1.8 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 DMSA
in vivo kit. (It reduces free pertechnetate into technetium of
+4 oxidation degree, which readily forms a complex entity with DMSA
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 DMSA 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-DMSA (DMSA labelled with radioactive Tc-99m radionuclide)
injection must be used within 3 hours from labelling.
6.4
Special precautions for storage
DMSA in
vivo kit is to be stored between 2°C and 8°C in its original packaging.
Tc-99m-DMSA 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
DMSA 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
DMSA
in vivo kit must not be used directly as an injection, only
Tc-99m-DMSA (Tc-99m radioisotope labelled DMSA) can be administered.
Tc-99m-DMSA 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 (1.0-1.8 GBq) is injected into
the vial through the rubber cap with a sterile syringe. Mix up the vial
thoroughly and the solution (or its appropriate portion) can be
administered intravenously.
pH value of the labelled product is 3.0-4.0 . It should be used within 3
hours from labelling. Within this period the quantity of the
radiochemical impurities should not exceed 15%.
Radiochemical purity of Tc-99m-DMSA should be determined with a Thin
Layer Chromatography test.
Determination of free pertechnetate (99mTcO4-) and
reduced, hydrolysed 99mTc in one step with Thin Layer
Chromatography:
Drop 5
µl of Tc-99m-DMSA solution on each of three ITLC-SG (Gelman Sciences,
cat. no.: 51432) plate of 1.5×20 cm size 1.5 cm from the end. With using
n-butanol saturated with 0.3 M hydrochloric acid solution as eluent
(n-butanol and 0.3 M hydrochloric acid solution are shaken together and
after separation the upper phase is taken) 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:
