3. PHARMACEUTICAL FORM
Sterile,
radioactive injection
4. CLINICAL PARTICULARS
4.1
Therapeutic indications
Field of
indication: Radionuclide therapy
Local, lesion specific treatment of neuroendocrine tumours, especially:
–
phaeochromocytoma
– neuroblastoma
– paraganglioma
– medullary thyroid carcinoma
– carcinoid
4.2
Posology and mode of administration
Dose: 3.3 –
4.1 GBq 131I-MIBG for one patient. Before beginning with the
examination blockage of the thyroid is recommended to prevent uptake of
free radioiodine evolving in vivo.
The ampoule containing 3.3-4.1 GBq activity represents a single dose of
a patient. The injection is to be administered slowly, during 2-4 hours,
therefore the product is not injected directly but its volume of 10 ml
is mixed with 90 ml of 5% glucose infusion and the total volume of 100
ml is administered slowly. Introduction of MIBG at once may cause blood
pressure increase, allergic symptoms, flushing or asthmatic spasms.
The MIBG-therapy can be monitored with an imaging technique, the gamma
camera pictures are usually taken in the 24th, 48th,
72nd and 96th hour after administration.
4.3
Contraindications
RELATIVE
CONTRAINDICATIONS
The use of the
product is relatively contraindicated
– At
the age below 18 years, except the indication of neuroblastoma
ABSOLUTE CONTRAINDICATIONS
The use
of the product is absolutely contraindicated
– in
case of pregnant or lactating women,
– if the patient does not provide an oral or written consent of being
treated with 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 to 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
Calcium
channel blocking agents, labetalol, reserpine, tricyclic
anti-depressants, phenyl-propanolamine and cimetidine may impede the
MIBG uptake, therefore, their application is to be suspended before
carrying out the examination.
4.6
Application during pregnancy and lactation
Application of the product during pregnancy and lactation is definitely
and absolutely contraindicated.
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 expectable if the
injection is administered faster than prescribed in paragraph 4.2. Such
in case blood pressure increase, allergic symptoms, flushing or
asthmatic spasms may occur to extremely different extent patient by
patient.
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.
In occurrence of an eventual overdose the effective absorbed radiation
dose is to be calculated with using the dosimetry table of the section
5.4 and the decision about the necessity and mode of further treatments
are to be made based on the result.
Pursuant to intravenous acute toxicity experiments on mice no clinical
symptoms can be observed up to 1.8 mg/kg body. If administered as
prescribed maximum 6 mg MIBG is introduced to the body, which is only
4.8% of the mentioned symptom free limit - calculated with an average
body weight of 70 kg. In case as the result of an error or a mistake of
the personnel the content of two vials are injected, it represents only
9.6% of the symptom free limit. Therefore, not the MIBG content but the
overdose of the radioactivity represents the relevant risk.
5. PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
ATC-code: V10X
A 02
Hormones produced by the adrenal medulla take part in the synthesis and
storage of catecholamine. Neuroendocrine tumours (phaeochromocytoma,
neuroblastoma, paraganglioma, medullary thyroid carcinoma, carcinoid)
consist of cells of analogous nature with those of the adrenal medulla
tissue. They excrete hormones specific to the adrenal medulla. Due to
the functional similarity of the adrenergic neurones and the chromaffin
cells of the adrenal medulla the molecules that are able to bind to the
receptors of the adrenergic terminal filaments are of anti-adrenergic
effect and they tend to be accumulated by the cells of the adrenal
medulla or other cells of similar type. Therefore, bretylium,
guanethidine and MIBG, which bears functional groups analogous to them,
are expected to bind to neuroendocrine receptors.
Since radioiodine labelled bretylium is unstable and guanethidine can
only be labelled with carbon, nitrogen or hydrogen isotopes while MIBG
can be labelled with radioiodine easily the latter has been introduced
to the clinical practice. 131I-MIBG strongly binds to the
chromaffin cells of the adrenal medulla and the uptake is proportional
to the density of the neuroendocrine receptors present. The MIBG uptake
may be hindered by cocaine and desmethyl-imipramine.
In aware of the maximum quantity of MIBG (6 mg) and activity (3.3-4.1
GBq) administered it is obvious that the therapy effect is not caused by
the pharmacodynamic features of MIBG but it is a result of the energy of
the beta particles emitted by 131I radionuclide, which is
transmitted at their absorption in the tissues and destroys the cells.
131I-MIBG leaves the body with the urine: 82% as intact
131I-MIBG, 16% as metabolised to meta-iodine-hippuric acid and 2%
as free radioiodine.
5.2
Pharmacokinetic properties
10-15% of
131I-MIBG introduced into the body appears in the cells with
functional relationship with the adrenal medulla tissues. 1 hour after
administration 131I-MIBG appears in the lungs, which it
leaves in 1-2 hours and binds to the neuroendocrine receptors of the
myocardium. The maximum radioactivity in the heart-muscle is observable
2-3 hours after administration, after 24 hours in the adrenal glands,
while 131I-MIBG accumulates in the neuroendocrine tumours and
metastases after 24-96 hours.
131I-MIBG not bound to the receptors leaves the body through
the kidneys and the urinary bladder (55% within 24 hours and 90% within
4 days).
5.3
Preclinical safety data
Pursuant to
acute toxicity studies* on mice no clinical symptoms are observed up to
20 times of the usual human dose (1.8 mg/kg body weight). The quantity
of the maximum dose of 131I-MIBG prescribed in the
Composition and Posology sections (6 mg / 70 kg body weight, i.e. 0.0857
mg/kg) represents only 4.8% of the symptom free limit. Therefore the
application of the product is considered safe.
* Radiopharmaceuticals product specification, Isopharma AS,
Institutetveien 18, N2007 Kjeller, Norway, 1996, p74.
5.4
Radiophysical properties of the radionuclide and the absorbed dose
values
6.2
Incompatibilities
Above all, the
product is incompatible with oxidising agents and chloride ions because
they assist the elimination of radioiodine from 131I-MIBG
molecule. For the same reason the product is to be kept frozen at –18°C.
Furthermore, another hazard of the strongly acidic medium that such in
circumstances the forming iodine is present in volatile status (radical
or elementary iodine), which may cause radioactive contamination in the
environment when opening the ampoule.
6.3 Shelf life
5 days from
the day of production.
6.4 Special
precautions for storage
The
product is to be stored in a freezer at -18°C; free from acidic vapours
and oxidative agents; using appropriate radiation shielding. Storage
conditions should be in accordance with the national regulations on
radioactive materials.
6.5 Nature and
composition of the packaging
131I-MIBG
solution is supplied in a so called lyophilising glass vial of 6 ml or
12 ml volume, closed with a rubber plug and an aluminium cap. A labelled
lead pot, which is capped with a lead cover and lined with a paper
cylinder as spacer, serves as radiation shielding. The glass vial is
placed in the paper cylinder and this way in the lead container as well.
The wall thickness of the lead pot varies between 15 and 30 mm according
to the activity of the solution contained. The labelled lead container
is put in a sealed and labelled metal can containing plastic foam
spacers. The can can be easily opened by tearing the top panel.
During delivery the frozen state is assured with cooling the package
with dry ice.
6.6
Instruction for use and handling
The
product is a radioactive preparation, which should be opened truly
according the following instructions:
During the operation the radiation safety regulations should be kept.
Tear off the top panel of the metal can. Remove the upper part of the
plastic foam spacer. Lift the lead container out of the metal can and
put it on the working area. Remove the seal strip and then the upper
part of the lead pot. This way the glass vial containing the radioactive
material is readily accessible.
Before beginning with the examination blockage of the thyroid is
recommended to prevent uptake of free radioiodine evolving in vivo.
The ampoule containing 3.3-4.1 GBq activity represents a single dose of
a patient. The injection is to be administered slowly, during 2-4 hours,
therefore the product is not injected directly but its volume of 10 ml
is mixed with 90 ml of 5% glucose infusion and the total volume of 100
ml is administered slowly. Introduction of MIBG at once may cause blood
pressure increase, allergic symptoms, flushing or asthmatic spasms.
The MIBG-therapy can be monitored with imaging techniques, the gamma
camera pictures are usually taken in the 24th, 48th,
72nd and 96th hour after administration.
Radiochemical purity of 131I-MIBG should be examined as
follows:
Drop 15 µl of 131I-MIBG solution on each of three
Polygram-SIL NHR strips of 1.5×20 cm size 1.5 cm from the end. With
using ethylacetate-ethanol mixture (1:1) as eluent let the front run
approximately up to 12-15 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:
131I-MIBG: 0.05-0.15
Free 131I: 0.80-1.00
Radiochemical purity is calculated with considering the peak areas.
Taking the total activity on the strip as 100% the activity ratio
corresponding to the peak of 131I-MIBG provides the
radiochemical purity data, which must be minimum 90% at expiry.
7. MARKETING AUTHORISATION HOLDER
Institute of
Isotopes Co., Ltd..
1121 Budapest, Konkoly Thege Miklós út 29-33.
1535 Budapest, P.O.B. 851.
8. NUMBER OF THE MARKETING AUTHORISATION
5512.46./1993.
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
Original Marketing Authorisation: June 28th, 1993
10. DATE OF REVISION OF THE TEXT
February 6th, 2003
