SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Sodium Chromate (⁵¹Cr) 37 MBq/ml radiopharmaceutical precursor, solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Sodium [⁵¹Cr]chromate :    37 MBq/ml

at the activity reference date The formulation contains: 3.1 to 31 pg/ml sodium chromate.

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.

This medicinal product contains:

Sodium: 3.55 mg/ml. This needs to be taken into consideration for patients on a controlled sodium diet.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Radiopharmaceutical precursor, solution

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

Sodium Chromate (⁵¹Cr) Solution 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, anaemias associated with splenomegaly, and “pseudoanaemia” secondary to an expanded plasma volume. Similarly red cell survival studies can be performed in patients with haemoglobinopathies, haemolytic anaemias and in whom there is a need to assess transfusion requirements after blood incompatibility reactions. Chromium-51 cell tagging may also be used to establish sites of cell sequestration (liver, spleen) particularly when considering splenectomy in patients with chromic haemolysis or idiopathic thrombocytopenic purpura.

Chromium-51 tagged erythrocytes may be used to quantify chronic gastrointestinal blood loss.

Posology and method of administration

Sodium Chromate (⁵¹Cr) is intended only for in vitro labelling of red blood cells which are subsequently re-injected into the patient.

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 washing the cells in isotonic saline or plasma. The cells are then re-suspended in saline before re-injection.

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 for administration to patients.

Estimation of red cell volume (RCV):

i.e.:

Estimation of red cell survival (RCS):

i.e.:

Red cell survival and sequestration:

i.e.:

Detection of gastrointestinal bleed:

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:	Newborn	1 year	5 year	10 year	15 year	18 year
weight	x 0.06	x 0.30	x 0.30	x 0.51	x 0.94	x 1.0
surface area	x 0.14	x 0.33	x 0.43	x 0.59	x 0.91	x 1.0

General correction factors have been advised as below

	3 kg	10 kg	20 kg	30 kg	40-50 kg	68 kg
Approx. age	Newborn	1 year	5 years	10 years	15 years	17 years+
adult dose	x 0.1	x 0.27	x 0.46	x 0.62	x 0.76 -0.88	x 0.99

The instructions for the preparation and determination of the concentration of this radiopharmaceutical can be found in section 12.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings and precautions for use

This product is not to be administered directly to the patient. The contents of the vial are intended only for the in vitro labelling of red blood cells for subsequent intravenous administration.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

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 woman 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 sodium [⁵¹Cr]chromate 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 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 effective dose.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

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 reasonable achievable bearing in mind the need to obtain the intended diagnostic or therapeutic result.

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 is less than 20 mSv. However, with this particular diagnostic agent only very low radiation doses are to be anticipated (ED<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 chromate-51. No cases of overdose have been reported to date.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Chromium is a potentially toxic substance. At higher doses, it inhibits glycolysis (>10 pg/ml and glutathione reductase (>5 pg/ml). At the dose used in cell labelling (<2 pg/ml of packed red cells) Sodium Chromate (⁵¹Cr) 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 [⁵¹Cr]chromate 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. Chromate-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 lifespan 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 intraluminal bleeding, is not re-absorbed 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 (not more than 10.8 pg chromate at 4 MBq) and also the tight binding of chromate-51 to haemoglobin makes for low systemic exposure during all envisaged diagnostic procedures.

6.1 List of excipients

Sodium chloride

Sodium chromate Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3    Shelf life

Not more than 75 days from the date of release. The reference date of the product is 60 days before expiry.

Once opened store in a refrigerator (2°C-8°C) and use within 8 hours.

Since the product does not contain an antimicrobial preservative and is marketed for multidose use, all doses from a single vial should be taken within a single working day and the product stored at 2°C-8^oC after removal of the first aliquot.

6.4    Special precautions for storage

Store below 25^oC. Do not freeze.

Storage procedures should be in accordance with national regulations for radioactive substances.

6.5 Nature and contents of container

10ml type I Ph.Eur., clear, colourless, borosilicate glass vial sealed with a PTFE-faced butyl rubber closure and oversealed with an aluminium overseal with central aperture. Each vial is packed within a radiation shielding container of lead metal and placed within a sealed metal tin.

Pack sizes: 37 MBq, 74 MBq, 185 MBq.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Normal safety precautions for handling radioactive materials should be observed. After use, all materials associated with the preparation and administration of radiopharmaceuticals, including any unused product and its container, should be decontaminated or treated as radioactive waste and disposed of in accordance with the conditions specified by the local competent authority. Contaminated material must be disposed of as radioactive waste via an authorised route.

7    MARKETING AUTHORISATION HOLDER

GE Healthcare Limited Amersham Place Little Chalfont Buckinghamshire United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00221/0111

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/09/2002 / 31/12/2006

10 DATE OF REVISION OF THE TEXT

18/11/2010

11 DOSIMETRY (IF APPLICABLE)

The table below shows the dosimetry as calculated according to the Publication 53 of the ICRP (International Commission on Radiological Protection, Radiation Dose to Patients from Radiopharmaceuticals, Pergamon Press 1987).

For this product the effective dose resulting from an administered activity of 4 MBq is typically 0.68 mSv (per 70 kg individual) (ICRP 80, 1998).

Dosimetry of chromate-51 labelled erythrocytes

Organ	Absorbed dose per unit activity administered (mGy/MBq)
	Adult	15 year	10 year	5 year	1 year
Adrenals	2.2E-01	2.7E-01	4.2E-01	6.5E-01	1.2E+00
Bladder wall	7.5E-02	9.7E-02	1.4E-01	2.2E-01	3.7E-01
	1.1E-01	2.5E-01	4.0E-01	6.2E-01	1.3E+00
Bone surfaces	9.9E-02	1.0E-01	1.7E-01	2.6E-01	4.6E-01
Breast		1.6E-01	2.4E-01	3.5E-01	6.0E-01
GI tract	1.4E-01 o no	1.2E-01	1.8E-01	2.8E-01	5.0E-01
Stomach wall	9.5E-02 9 4E-02	1.2E-01	1.7E-01	2.8E-01	4.9E-01
		1.0E-01	1.6E-01	2.3E-01	4.2E-01
Small intestine	8.1E-02	6.1E-01	9.1E-01	1.4E+00	2.4E+00
	5.1E-01
ULI wall
LLI wall
Heart
Kidneys	2.2E-01	2.6E-01	4.1E-01	6.4E-01	1.2E+00
Liver	2.4E-01	2.9E-01	4.6E-01	6.9E-01	1.3E+00
	3.2E-01	4.1E-01	6.5E-01	1.0E+00	2.0E+00
Lungs	8.2E-02	1.1E-01	1.6E-01	2.5E-01	4.5E-01
Ovaries	1.9E-01	2.2E-01	3.4E-01	5.0E-01	8.5E-01
Pancreas
Red marrow	1.4E-01	1.7E-01	2.6E-01	4.1E-01	7.6E-01
	1.6E+00	2.1E+00	3.3E+00	5.1E+00	9.3E+00
Spleen	6.3E-02	7.7E-02	1.1E-01	1.7E-01	3.3E-01
Testes	1.2E-01	1.6E-01	2.6E-01	4.2E-01	7.9E-01
Thyroid	8.5E-02	1.1E-01	1.6E-01	2.5E-01	4.5E-01
Uterus
Other tissue	8.5E-02	1.0E-01	1.5E-01	2.3E-01	4.2E-01
Effective
dose equivalent	2.6E-01	3.3E-01	5.2E-01	8.0E-01	1.5E+00

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

This radiopharmaceutical may be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the local competent official organisations (see section 6.6).

The administration of radiopharmaceuticals creates risks for 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.

Procedure for determination of red cell volume

Sodium Chromate (⁵¹Cr) Solution should be used without dilution.

The procedure described is for labelling the patient’s own red blood cells.

The following method describes the use of 25 ml blood. With experience it may be possible to adjust this procedure in order to halve the volume of blood used at stage 2.

1.    Draw 25 ml of blood from the patient in a heparinised syringe. Place 5 ml in a counting tube, add a small amount of powdered saponin and mix to a haemolyse the cells. This sample (sample 1) is used to measure the background radiation.

2.    Place the remaining blood (20 ml) in a sterile bottle which contains 4 ml of standard ACD solution.

3.    Mix the blood and ACD solution, add 0.74-1.11 MBq (20-30 pCi) of Sodium Chromate (⁵¹Cr) Solution) slowly with continuous gentle mixing. 3.7 MBq (100 pCi) is added if red cell survival time is being determined simultaneously-see below).

4.    Leave for 30 minutes at room temperature.

5.    Add 50 mg of ascorbic acid (as sterile injection solution) to reduce unbound chromate to the trivalent state.

6. Add 40 ml of sterile isotonic saline to wash. Invert gently 10-12 times.

8. Remove and discard the supernatant liquid, then reconstitute to 20 ml with sterile isotonic saline.

9.    Dilute a 1 ml aliquot of the resuspended labelled cells to 1000 ml with distilled water or saline containing saponin (to haemolyse the cells). Measure a 5 ml aliquot of this solution to serve as a standard (sample 2).

10.    Inject intravenously an aliquot of the undiluted, resuspended labelled red cells containing the required quantity of radioactivity. The volume (V) of this aliquot is determined accurately by weighing the syringe and needle before and after injection.

11.    Allow 10 minutes for mixing of the labelled cells within the vascular system. Increasing this period to 30-40 minutes for polycythaemia and splenomegaly.

12.    Withdraw without stasis into a heparinised syringe an 8 ml sample of blood from the arm opposite to that used for the injection of the labelled cells. Place 5 ml of this in a counting tube, and mix in a small amount of powdered saponin to haemolyse the cells (sample 3).

13.    Use the remainder of the 8 ml to obtain duplicate haematocrit readings (H).

14.    Count the radioactivity (cpm) for samples 1-3, and on empty vial (sample 4) for ambient background radiation.

15.    Calculate the total red cell volume from the formula:

R= 1000(S-B) x V x H x F (P-A) x 100

where    R = total red cell volume (ml)

A = cpm for sample 1 (patient background)

S = cpm for sample 2 (standard)

P = cpm for sample 3 (post-injection sample) B = cpm for sample 4 (ambient background) V = volume (ml) injection at stage 10 H = haematocrit (per cent)

F = correction factor (about 0.96) to correct the haematocrit value for plasma trapped with the red cells. No correction factor is required if a microhaematocrit is used.

16. Calculate, if required, the approximate total blood volume (T) from the formula: T = R x 100

H x F x 0.91

The corrected haematocrit is multiplied by 0.91 to compensate for the non-uniformity of the distribution of the red cells throughout the circulation. However, this factor of 0.91 is inaccurate in many disease states and in pregnancy (due to alteration in the circulatory volume), and the values for T obtained by this method is therefore only an approximation.

Procedure for determination of red cell survival time

The procedure described follows Method C in the report on Recommended Methods for Radioisotope Red Cell Survival Studies by The International Committee for Standardisation in Haematology (Brit. J Haemat. 1971, vol 21, pp 378-386). Methods A or B in that report can also be employed.

If red cell volume is being determined simultaneously, follow stages 1-5 of the procedure described above, with these variations:

i.    if leucocyte count exceeds 25,000/ml centrifuge the mixture of blood and ACD solution, separate plasma, remove buffy coat and then replace plasma.

ii.    add 3.7 MBq (100pCi) Sodium Chromate (⁵¹Cr) Solution at stage 3.

iii.    divide the suspension of labelled cells on completion of stage 5.

If only red cell survival time is being determined follow the procedure in stages 2-5 (above, but mix 10 ml of the patient’s blood with 2 ml of the ACD solution and add 1.48-1.85 MBq (40-50 pCi) of Sodium Chromate (⁵¹Cr) Solution. There is no washing stage. After adding ascorbic acid at stage 5 allow to stand for 3 minutes, then continue thus: 6. Inject intravenously the required volume of the labelled blood mixture.

7. At 10 minutes take a 7-10 ml blood specimen into a heparinised syringe from a vein other than that used for injection. (When it is suspected that mixing will be incomplete in 10 minutes take this specimen at 60 minutes.)

9. Take a further specimen at 24 hours, three specimens between day 2 and day 7, and thereafter at least 2 specimens per week for the duration of the study.

10. Measure the haemoglobin (g/100 ml) by the haemiglobincyanide method or the PCV on a part of each specimen.

11. Add a small amount of saponin to each sample, mix well to ensure haemolysis hen pipette 1-3 ml into a counting tube. Store samples at 2-4°C.

12. On the final day of the study count the radioactivity of each sample and also of the plasma sample from the 10 minute (or 60 minute) specimen and of an empty tube for background subtraction. The values obtained are expresses as cpm/ml of red blood cells.

13. Correct the cpm figures for physical decay then plot the data in accordance with the directions on pages 383-384 of the International Committee report on Radioisotope Red Cell Studies. These give a detailed analysis of red cell survival data and a table of mean Cr survival and correction factors. The time taken for half the label to leave the circulation (T_J/2 or T₅₀ Cr) was commonly used as a single index. However, the International Committee’s report emphasises that the T₅₀Cr has no simple relationship to the mean red cell life span, which is the parameter required in clinical practice.

Radioactivity

The radioactive concentration of Sodium Chromate (⁵¹Cr) Solution at 1200 GMT on the day of administration is calculated by multiplying the radioactive concentration at reference, as shown on the label, by the appropriate factor as shown in the following table:

Day*	Factor	Day*	Factor	Day*	Factor
-28	2.015	-4	1.105	20	0.606
-26	1.917	-2	1.051	22	0.577
-24	1.823	0	1.000	24	0.549
-22	1.734	2	0.951	26	0.522
-20	1.649	4	0.905	28	0.496
-18	1.569	6	0.861	30	0.472
-16	1.492	8	0.819	35	0.417
-14	1.419	10	0.779	40	0.368

-12	1.350	12	0.741	45	0.324
-10	1.284	14	0.704	50	0.286
-8	1.222	16	0.670	55	0.253
-6	1.162	18	0.637	60	0.223

"Days

before (-) or days after the reference date stated on the container label.