3. PHARMACEUTICAL FORM
Pharmaceutical
form of MDP in vivo kit: Powder for injection
Pharmaceutical form of Tc-99m-MDP: Radioactive, sterile injection
4. CLINICAL PARTICULARS
4.1
Therapeutic indications
This medical
product is for DIAGNOSTIC purposes only.
Field
of indication: isotope diagnostic bone scintigraphy
Application is especially recommended in case of the following diseases:
– Primer bone tumour
– Bone metastases of other tumours (e.g. prostate, breast and lung
cancer)
– Osteomyelitis
– Metabolic diseases of the bone
– Paget’s disease
4.2 Posology
and mode of administration
The quantity
of Tc-99m-MDP prepared at one labelling can be divided into 3-6
individual doses. In order each patient can obtain the required activity
of 370-740 MBq at the time of application the labelling should be
carried out with 3.0-6.0 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-MDP is
administered to the patient as intravenous injection. Taking the bone
scintigraphy exposure (total body, targeted or SPECT exposure) should
begin 2-4 hours after injection.
4.3
Contraindications
RELATIVE CONTRAINDICATIONS
The use of the product is relatively 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 CONTRAINDICATIONS
The use of the product is absolutely contraindicated
– 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
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 0.83 mg, maximum 1.67 mg of MDP is
introduced to the body. Pursuant to intravenous acute toxicity
experiments on mice no clinical symptoms can be observed up to 9 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 5 mg, which is
0.0714 mg/kg body for a patient of average weight (70 kg). This equals
to 0.8% of the symptom-free toxicity level. Consequently, no toxic
effect is expectable in overdose.
5. PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
ATC
code: V09B A 02
After administered intravenously Tc-99m-MDP (like other
Tc-99m-diphosphonates, e.g. hydroxy-methylene-diphosphonate,
1-hydroxy-ethylidene-1,1-diphosphonate) leaves the blood and
concentrates mainly in the skeleton and to a negligible extent in the
soft tissues. The mechanism of the 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 –PO3H2
groups of MDP 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 excellent imaging.
A much smaller quantity of injected Tc-99m-MDP binds to the blood plasma
proteins, which results in a very slight body background. Tc-99m-MDP not
bound to the skeleton washes out from the body in the urine. Washout
through the hepatobiliary system is negligible.
It is a general observation that in patients approximately half of the
injected activity binds to the skeleton. In case of the healthy this
value usually does not exceed 31%. However, in presence of bone
metastases almost 40% of the total activity accumulates in metastases,
therefore, metastases conspicuously shows up against the background on
the image of the skeleton. The same applies to fractures, inflammations,
osteoporosis and hyper-parathyroidism.
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. There
should have no or only a negligible effect upon bone formation. The
medical product meets this requirement since minimum 0.83 mg, maximum
1.67 mg Tc-99m-MDP is administered, whose pharmaceutical and
pharmacodynamic effect cannot be observed.
5.2
Pharmacokinetic properties
Tc-99m-MDP
introduced intravenously leaves the bloodstream in three steps:
– Quick phase T1/2 = 3.5 min
– Medium phase T1/2 = 27 min
– Slow phase T1/2 = 144 min
During the quick phase Tc-99m-MDP is excreted to the extravascular
space. The medium phase corresponds to bone uptake. The slow phase is
the dissociation of Tc-99m-MDP bound to plasma proteins of blood.
Maximum bone uptake ensues 1-2 hours after injection and remains
unchanged approximately 72 hours.
Washout proceeds with urine. Maximum activity appears in the kidneys 20
minutes after injection. At normal kidney function approximately 32% of
the whole administered activity filtrated out in glomerular way, 47% of
it shows up within 2 hours in the urine, 60% within 6 hours. Activity
observable in the liver and the intestines is insignificant.
5.3
Preclinical safety data
Pursuant to
intravenous acute toxicity experiments on mice no clinical symptoms can
be observed up to 9 mg/kg body. If administered as prescribed minimum
0.83 mg, maximum 1.67 mg of MDP 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 5 mg, which is 0.0714 mg/kg body
for a patient of average weight (70 kg). This equals to 0.8% of the
symptom-free toxicity level. Consequently, application of the medical
product can be considered safe from the point of view of toxicity.
Further advantage of the medical product is that the activity of the
applied Tc-99m-pertechnetate (in the range of 3-6 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 MDP in
vivo kit. (It reduces free pertechnetate into technetium of +4
oxidation degree, which readily forms a complex entity with MDP 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 handling any use of the
product.
No interaction with other pharmaceuticals has been reported.
6.3
Shelf life
Shelf
life of MDP 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-MDP (MDP labelled with radioactive Tc-99m radionuclide) injection
must be used within 3 hours from labelling.
6.4
Special precautions for storage
MDP
in vivo kit is to be stored in a refrigerator (2-8°C) in its
original packaging.
Tc-99m-MDP 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
MDP
in vivo kit contains the components shown in paragraph 2.a and 6.1
as sterile, pyrogen-free freeze dried material. Each ampoule 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
MDP
in vivo kit must not be used directly, only Tc-99m-MDP (Tc-99m
radioisotope labelled MDP) can be administered. Tc-99m-MDP 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 (3-6 GBq) is injected into the
vial through the rubber cap with a sterile syringe (minimum volume: 2
ml, maximum volume: 5 ml). 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%. Radiochemical purity of
Tc-99m-MDP 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-MDP 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 Tc-99m-MDP 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-MDP 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 0.3-0.4
Labelled complex Tc-99m-MDP and free 99mTcO4-:
0.7-1.0 0.7-1.0
Radiochemical purity (H) is calculated with the following formula:
