Download Initialer - Produktresume

29. april 2004
SUMMARY OF PRODUCT CHARACTERISTICS
Bristol-Myers Squibb Sodium Chromate (Cr-51) Sterile Solution
1.
NAME OF THE MEDICINAL PRODUCT
Bristol-Myers Squibb Sodium Chromate (Cr-51) Sterile Solution
Code: Cr-51 (VI) PRE
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
The active ingredient is sodium chromate (Cr-51) - 37 and 370 MBq/ml at calibration time.
Specific Activity:  370 MBq/mg of chromate ion at expiry.
Chromium-51 has a physical half-life of approximately 28 days and decays by electron capture
emitting gamma radiation with an energy of 0.32 MeV.
3.
PHARMACEUTICAL FORM
Precursor solution.
4.
CLINICAL PARTICULARS
4.1. Diagnostic indications
Sodium chromate (Cr-51) is used for in-vitro ex-vivo red blood cell labelling and is intended only
for diagnostic use.
The radio labelling of erythrocytes facilitates the determination of red cell volume, for example, in
the diagnosis of polycythaemias, anaemia’s associated with splenomegaly, and “pseudoanaemia”
secondary to an expanded plasma volume. Similarly red cell survival studies can be performed in
patients with haemoglobinopathies, haemolytic anaemia’s and in whom there is a need to assess
transfusion requirements after blood incompatibility reaction. (Cr-51)-cell tagging may also be
used to establish sites of cell sequestration (liver, spleen) particularly when considering splenectomy in patients with chronic haemolysis or idiopathic trombocytopenic purpura.
(Cr-51)-tagged erythrocytes may be used to quantify chronic gastrointestinal blood loss.
4.2. Posology and method of administration
Sodium chromate (Cr-51) solution is intended only for the in-vitro labelling of red blood cells
which are subsequently re-injected into the patient.
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For red cell volume and survival, 10 - 15 ml of blood is removed by venesection and centrifuged
and the red cells incubated with the radioactive solution. To minimise damage to red cells, blood
pH should be maintained using appropriate additives. Excess unbound isotope may be removed by
removed by washing the cells in isotonic saline or plasma. The cells are then re-suspended in saline
before re-injection.
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Serial blood samples may then be subsequently removed for counting and radiokinetic calculations.
Sequestration sites in the body are identified by external counting. In chronic gastrointestinal
bleeding the activity in venous blood is compared to that in the faeces.
The following activities for red cell labelling are those recommended by the International Committee for Standardisation in Haematology (ICSH) for administration to patients.
Estimation of red cell volume (RCV):
3.7 - 7.4 kBq / kg body weight
i.e. 260-520 kBq /
70 kg individual
Estimation of red cell survival (RCS):
 18.5 kBq / kg body weight
i.e. 740 - 1300
kBq/70 kg individual
 50 kBq / kg body weight
Red cell survival and sequestration:
i.e.  4 MBq / 70
kg individual
Detection of gastrointestinal bleed:
0.74 - 4 MBq / 70 kg individual
Paediatric administration:
Detailed biodistribution data in children are not available. However, in keeping with normal practice, the activities administered to children should be derived fractions of those advised in adults.
These are calculated according to body weight or surface area. The activities proposed below are
based upon averaged data and offered only as guidance.
Advised paediatric regimens expressed as a proportion of recommended adult activities
Factor based on
body
weight
surface area
New born
1 year
5 years
10 years
15 years
18 years
x 0.06
x 0.14
x 0.30
x 0.33
x 0.30
x 0.43
x 0.51
x 0.59
x 0.94
x 0.91
x 1.0
x 1.0
General correction factors have been advised also by paediatric task group of the European Association of Nuclear Medicine*.
PTG
EANM*
approx. age
adult dose
3 kg
10 kg
20 kg
30 kg
40-50 kg
68 kg
New-born
x 0.1
1 year
x 0.27
5 years
x 0.46
10 years
x 0.62
15 years
x 0.76-0.88
17 years+
x 0.99
4.3. Contra-indications
None known.
4.4. Special warnings and precautions for use
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This product is a radioactive material. It should be received, used and administered only by authorised persons in designated clinical settings. Its receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the local competent official organisations.
4.5. Interactions with other medicaments and other forms of interaction
None have been described.
4.6. Pregnancy and lactation
Women of Childbearing Potential:
When it is necessary to administer radioactive medicinal products to women of childbearing potential, information should always be sought about pregnancy. Any woman who has missed a period
should be assumed to be pregnant until proven otherwise. Where uncertainty exists it is important
that radiation exposure should be the minimum consistent with achieving the desired clinical information. Alternative techniques which do not involve ionising radiation should be considered.
Pregnancy
Radionuclide procedures carried out on pregnant women also involve radiation doses to the foetus.
In particular, activities delivering doses of  0.5 mGy to the uterus are considered hazardous. Only
imperative investigations should be carried out during pregnancy, when the likely benefit exceeds
the risk incurred by mother and foetus. The expected absorbed dose to the uterus after administering an activity of 4 MBq chromate Cr-51 has been estimated to be 0.4 mGy although lower activities would normally be utilised. Teratogenic effects are also reported to have been described after
repeated administration of chromium (III) salts in animal studies. Chromium-51 has a physical
half-life of 28 days. As chromate it is rapidly excreted in the urine but when bound to cells it has an
effective half-life similar to its physical half-life. Nevertheless, in view of the likely maximal
chemical concentrations and radioactivities administered in the context of the described haematological investigations, and the tight intracellular binding of the label in-vivo, advice on the avoidance of pregnancy need only extend until commencement of the next complete menstrual cycle.
Lactation
Before administering a radioactive medicinal product to a mother who is breast feeding consideration should be given as to whether the investigation could be reasonably delayed until the mother
has ceased breast feeding and as to whether the most appropriate choice of radiopharmaceutical has
been made, bearing in mind the secretion of activity in breast milk. There are no data relating to the
excretion of the chromium-51 after cell labelling in breast milk. Where such investigation is considered mandatory the monitoring of breast milk radioactivity may be indicated. The suckling infant should not receive ingested activities which would lead to overall exposures in excess of 1 mSv
(EDE).
4.7. Effects on ability to drive and use machines
Effects on ability to drive or use machines have not been described and are not expected in view of
the small chemical doses likely to be administered.
4.8. Undesirable effects
For each patient, exposure to ionising radiation must be justifiable on the basis of likely benefit.
The activity administered must be such that the resulting radiation dose is as low as reasonably
achievable bearing in mind the need to obtain the intended diagnostic or therapeutic result.
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Exposure to ionising radiation is linked with cancer induction and a potential for development of
hereditary defects. For diagnostic nuclear medicine investigations the current evidence suggests
that these adverse effects will occur with low frequency because of the low radiation doses incurred.
For most diagnostic investigations using a nuclear medicine procedure the effective dose equivalent
(EDE) is less than 20 mSv. However, with this particular diagnostic agent, only very low radiation
doses are to be anticipated (EDE < 1 mSv).
No adverse effects have been described after the administration of chromium labelled blood cells
despite clinical use over several decades.
4.9
Overdose
This agent is intended for use by competent personnel within an appropriate clinical setting. As
such the possibility of overdose is highly unlikely. However, in the event of inadvertent administration of a significant excess of radioactivity, for example during red cell labelling, haematological
monitoring over several months could be necessary. It is not possible to promote the excretion of
the cell bound Cr-51. No cases of overdose have been reported to date.
5.
PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
ATC code : V09G X03
Chromium is a potentially toxic substance. At higher doses, it inhibits glycolysis (> 10 g/ml) and
glutathione reductase (> 5g/ml). At the dose used in cell labelling (<< 2g/ml of packed red cells)
sodium chromate (Cr-51) solution has no effect on the cell to which it is bound nor does it appear to
exert other significant pharmacodynamic effects in man.
5.2. Pharmacokinetic properties
The hexavalent form of sodium chromate (Cr-51) is normally used to radiolabel erythrocytes. Reduction to the trivalent form can be effected by washing with agents such as ascorbic acid thus enabling tight binding to the beta-chain of haemoglobin. (Cr-51) is thus released only on the death of
the red cell. Other types of binding are less stable and about 1 % of the radio label may elute from
the cells daily after injection into the bloodstream. Cumulative loss by elution may be as high as 40
% over the life span of the erythrocytes.
The chromium released is eliminated predominantly by the kidneys (96 %) and is not taken up by
other cells. Any radiolabel carried into the gastrointestinal tract, due to intra luminal bleeding, is
not reabsorbed into the systemic circulation.
5.3. Preclinical safety data
Although the toxic effects of high chemical doses of chromium compounds are described, the relatively small amounts utilised in cell labelling (< 0.0108 mg at 4 MBq at expiry) and also the tight
binding of (Cr-51) to haemoglobin makes for low systemic exposure during all envisaged diagnostic procedures.
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5.4. Radiation dosimetry
The estimated absorbed dose in adults for various conditions of administration are given below.
These are quoted from ICRP 53.
For this product the effective dose equivalent resulting from an administered activity of 4 MBq is
typically 1 mSv (per 70 kg individual).
Dosimetry (Cr-51) - labelled erythrocytes
T1/2 = 27.7 days
Organs
Absorbed dose
per unit activity administred (mGy/MBq)
Adult
Adrenals
Bladder walls
Bone surface
Breast
Intestinal tract
Stomach wall
Small intestine
Upper large intestine wall
Lower large intestine wall
Heart
Kidneys
Liver
Lungs
Ovaries
Pancreas
Marrow
Spleen
Testicles
Thyroid
Uterus
Other tissues
Effective equivalent dose
(mSv/MBq)
6.
2.2 x 10-1
7.5 x 10-2
1.1 x 10-1
9.9 x 10-2
1.4 x 10-1
9.5 x 10-2
9.4 x 10-2
8.1 x 10-2
5.1 x 10-1
2.2 x 10-1
2.4 x 10-1
3.2 x 10-1
8.2 x 10-2
1.9 x 10-1
1.4 x 10-2
1.6 x 10+0
6.3 x 10-2
1.2 x 10-1
8.5 x 10-2
8.5 x 10-2
2.6 x 10-1
PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Sodium chloride
Water for injection
6.2. Incompatibilities
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None known.
6.3. Shelf-life
The expiry date for this product is up to 6 weeks after the calibration date (up to 8 weeks after the
production date). The expiry date is stated on the label.
The product does not contain any preservative agent. In case of multi-dose use of the product, it is
advisable to limit the use of the product to one working day.
6.4. Special precautions for storage
The product should be stored in its original container and under appropriate shielding at 2 - 8°C.
Storage procedures should be in accordance with national regulations for radioactive substances.
6.5. Nature and contents of container
Bristol-Myers Squibb Sodium Chromate(Cr-51) Sterile Solution is in the form of a sterile isotonic
solution in type I glass multi-dose bottles with a bromobutyl rubber stopper and an aluminium
overseal.
6.6. Instructions for use/handling
Withdrawals have to be performed under aseptic conditions.
The administration of radiopharmaceuticals creates risks to other persons, from external radiation or
contamination from spills of urine, vomiting, etc. Radiation protection precautions in accordance
with national regulations must therefore be taken.
7.
MARKETING AUTHORIZATION HOLDER
Bristol-Myers Squibb Pharma Belgium Sprl
Chaussée de la Hulpe 185
B-1170 Brussels
Belgium
8.
MARKETING AUTHORIZATION NUMBER
DK R. 1074
9.
DATE OF FIRST AUTHORIZATION/RENEWAL OF AUTHORIZATION
13 February 1995/24 January 2000
10.
DATE OF (PARTIAL) REVISION OF THE TEXT
January 2002.
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9.
Dato for første markedsføringstilladelse
13. februar 1995
10.
Revision af produktresumé
29. april 2004
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