Pharmaceutical particulars : מידע רוקחי

6.    PHARMACEUTICAL PARTICULARS

6.1   List of excipients
Sodium chloride
Stannous chloride dihydrate

6.2   Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 8.

6.3   Shelf Life

The expiry date of the product is indicated on the packaging materials 
Store the reconstituted product below 25oC. Do not freeze or refrigerate. The labelled product must be injected within 30 minutes of reconstitution.

6.4   Special precautions for storage

Store below 25oC. Do not refrigerate or freeze.
Storage should be in accordance with national regulations for radioactive materials.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5   Nature and contents of container

10mL glass vial sealed with a chloro-butyl rubber closure and over sealed with an aluminum over-seal with a blue flip off cap.

Pack sizes: kit contains 2 or 5 vials

Not all pack sizes may be marketed.
6.6   Special precautions for disposal and other handling


General warning
Radiopharmaceuticals 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 competent official organisation.

Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

Contents of the vial are intended only for use in the preparation of technetium (99mTc) exametazime injection and are not to be administered directly to the patient without first undergoing the preparative procedure.
For instructions on reconstitution of the medicinal product before administration, see section 8.

If at any time in the preparation of this product the integrity of this vial is compromised it should not be used. Administration procedures should be carried out in a way to minimise risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

The content of the kit before reconstitution is not radioactive. However, after sodium pertechnetate (99mTc), Ph.Eur. is added, adequate shielding of the final preparation must be maintained.

The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spill of urine, vomiting etc. Radiation protection precautions in accordance with national regulations must therefore be taken.
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 local requirements

7.   DOSIMETRY

Technetium (99mTc) is produced by means of a (99Mo/99mTc) generator and decays with the emission of gamma radiation with a mean energy of 140 keV and a half-life of 6.02 hours to technetium (99Tc) which, in view of its long half-life of 2.13 x 105 years can be regarded as quasi stable.

(1)     Brain scintigraphy
The table below shows the dosimetry as calculated according to the Publication 62 of the ICRP (International Commission on Radiological Protection in Biomedical Research, Pergamon Press 1991) following administration of technetium 99mTc-exametazime to adults.
Absorbed dose per unit activity administered (mGy/MBq)
Organ                               Adult
Adrenals                              5.3E - 03
Bladder                               2.3E - 02
Bone surfaces                         5.1E - 03
Brain                                 6.8E - 03
Breast                                2.0E - 03
Gall bladder                          1.8E - 02

GI tract
Stomach                             6.4E - 03
SI                                  1.2E - 02
ULI                                 1.8E - 02
LLI                                 1.5E - 02

Heart                                  3.7E - 03
Kidneys                                3.4E - 02
Liver                                  8.6E - 03
Lungs                                  1.1E - 02
Muscles                                2.8E - 03
Oesophagus                             2.6E - 03
Ovaries                                6.6E - 03
Pancreas                               5.1E - 03
Red marrow                             3.4E - 03
Skin                                   1.6E - 03

Spleen                                 4.3E - 03
Testes                                 2.4E - 03
Thymus                                 2.6E - 03
Thyroid                                2.6E - 02
Uterus                                 6.6E - 03

Remaining organs                       3.2E - 03
Effective dose                         9.3E-03
(mSv/MBq)
Effective Dose is 4.7 mSv/500 MBq (70kg individual)

(2)   In vivo localisation of technetium-99m-labelled leucocytes

The table below shows the dosimetry as calculated according to the Publication 80 of the ICRP (International Commission on Radiological Protection, Radiation Dose to Patients from Radiopharmaceuticals, Pergamon Press 1998.
Organ                           Absorbed dose per unit activity administered (mGy/MBq)
Adult          15 years      10 years      5 years    1 year
Adrenals       1.0E-02        1.2E-02       1.8E-02       2.6E-02    4.3E-02 Bladder        2.6E-03        3.5E-03       5.2E-03       7.8E-03    1.4E-02 Bone           1.6E-02        2.1E-02       3.4E-02       6.1E-02    1.5E-01 surfaces
Brain          2.3E-03        2.9E-03        4.4E-03      7.0E-03    1.3E-02 Breast         2.4E-03        2.9E-03        4.9E-03      7.6E-03    1.3E-02 Gall bladder   8.4E-03        1.0E-02        1.6E-02      2.5E-02    3.6E-02 GI-tract
Stomach      8.1E-03        9.6E-03        1.4E-02      2.0E-02    3.2E-02 SI       4.6E-03        5.7E-03        8.7E-03      1.3E-02    2.1E-02 Colon      4.3E-03        5.4E-03        8.4E-03      1.2E-02    2.1E-02 ULI       4.7E-03        5.9E-03        9.3E-03      1.4E-02    2.3E-02 LLI       3.7E-03        4.8E-03        7.3E-03      1.0E-02    1.8E-02 
Heart          9.4E-03        1.2E-02        1.7E-02      2.5E-02    4.4E-02 Kidneys        1.2E-02        1.4E-02        2.2E-02      3.2E-02    5.4E-02 Liver          2.0E-02        2.6E-02        3.8E-02      5.4E-02    9.7E-02 Lungs          7.8E-03        9.9E-03        1.5E-02      2.3E-02    4.1E-02 Muscles        3.3E-03        4.1E-03        6.0E-03      8.9E-03    1.6E-02 
Oesophagus     3.5E-03        4.2E-03        5.8E-03      8.6E-03    1.5E-02 Ovaries        3.9E-03        5.0E-03        7.2E-03      1.1E-02    1.8E-02 Pancreas       1.3E-02        1.6E-02        2.3E-02      3.4E-02    5.3E-02 Red marrow     2.3E-02        2.5E-02        4.0E-02      7.1E-02    1.4E-01 Skin           1.8E-03        2.1E-03        3.4E-03      5.5E-03    1.0E-02 
Spleen         1.5E-01        2.1E-01        3.1E-01      4.8E-01    8.5E-01 Testes         1.6E-03        2.1E-03        3.2E-03      5.1E-03    9.2E-03 Thymus         3.5E-03        4.2E-03        5.8E-03      8.6E-03    1.5E-02 Thyroid        2.9E-03        3.7E-03        5.8E-03      9.3E-03    1.7E-02 Uterus         3.4E-03        4.3E-03        6.5E-03      9.7E-03    1.6E-02 Remaining      3.4E-03        4.2E-03        6.3E-03      9.5E-03    1.6E-02 organs
Effective      1.1E-02        1.4E-02        2.2E-02      3.4E-02    6.2E-02 dose
(mSv/MBq)

Effective Dose is 2.2 mSv/200 MBq (70 kg individual).
8.   INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS
Withdrawals should be performed under aseptic conditions. The vials must not be opened before disinfecting the stopper, the solution should be withdrawn via the stopper using a single dose syringe fitted with suitable protective shielding and a disposable sterile needle or using an authorised automated application system. If the integrity of this vial is compromised, the product should not be used.

Procedure for preparation of technetium-99m exametazime for intravenous injection or in vitro leucocyte labelling:
Use aseptic technique throughout

(1)     Place the vial in a shielding container and swab the closure with the sanitising swab provided.

(2)     Using a 10ml syringe inject into the shielded vial 5ml of sterile eluate from a- technetium-99m generator (see notes 1-6). Before withdrawing the syringe from the vial, withdraw 5ml of gas from the space above the solution to normalise the pressure in the vial. Shake the shielded vial for 10 seconds to ensure complete dissolution of the powder.

(3)     Assay the total activity and calculate the volume to be injected or used for in vitro technetium-99m-leucocyte labelling.

(4)     Complete the label provided and attach to the vial.

(5)     Use within a maximum of 30 minutes after reconstitution. Discard any unused material.

Note:

(1)     For the highest radiochemical purity reconstitute with freshly eluted technetium-99m generator eluate.

(2)     Use only eluate, which was eluted less than 2 hours previously from a generator, which was eluted within 24 hours.

(3)     0.37 – 1.11 GBq (10-30mCi) technetium-99m may be added to the vial.

(4)     Before reconstitution the generator eluate may be adjusted to the correct radioactive concentration (0.37 – 1.11GBq in 5ml) by dilution with Sodium Chloride for injection.

(5)     Pertechnetate complying with the specifications prescribed by the USP and BP/Ph. Eur. Monographs on Sodium Pertechnetate (99mTc) Injection should be used.
(6)    The pH of the prepared injection/labelling agent is in the range 9.0 – 9.8.

Procedure for separation of leucocytes and subsequent in vitro labelling with technetium- 99m exametazine

Use aseptic technique throughout

(1)    Draw 9 mL of acid-citrate-dextrose (ACD) (see note a) into each of two 60 mL plastic non-heparinized syringes.

(2)    Withdraw 51 mL of patient’s blood into each syringe, using a 19 G Butterfly needle infusion set. Close the syringes with sterile hubs.

(3)    Dispense 2 ml sedimentation agent (see note b) into each of 5 Universal containers or tubes.

(4)    Without attaching a needle to the syringes dispense 20 mL of blood into each of the 5 Universal tubes containing sedimentation agent. Dispense the remaining 20 mL of blood into a tube without sedimentation agent.

TIP: To avoid bubbles and frothing run the blood gently down the sides of the tubes.

(5)    Mix the blood and sedimentation agent with one gentle inversion. Remove the cap of the Universal tube and burst the bubble formed at the top using a sterile needle. Replace the cap and allow the tubes to stand for 30-60 minutes for erythrocyte sedimentation to take place.

TIP: The period of time for erythrocyte sedimentation depends on the patient’s condition.
As a guideline it should be stopped when the blood has sedimented to give approximately half the volume as sedimented red cells.

(6)    Meanwhile centrifuge the tube containing 20 mL of blood and no sedimentation agent at 2000 g for 10 minutes. This will yield supernatant cell-free plasma CFP containing ACD which is retained, at room temperature, for use as a cell labelling and re-injection medium.

(7)    When sufficient red cells sedimentation has taken place [see (5)] carefully transfer 15ml aliquots of the cloudy straw-coloured supernatant into clean Universal tubes. Take care to avoid withdrawing any sedimented erythrocytes.
The supernatant is leucocyte-rich, platelet-rich plasma [LRPRP]

TIP Do not use needles on sampling syringes to avoid unnecessary cell damage.

(8)    Centrifuge the LRPRP at 150 g for 5 minutes to give supernatant, platelet-rich plasma (PRP) and a pellet of “mixed” leucocytes.
(9)    Remove as much of the PRP as possible into clean Universal tubes and further centrifuge at 2000g for 10 minutes to give more supernatant, CFP containing sedimentation agent. This will be used to wash the cells after labelling.

(10)   Meanwhile loosen the pellets of ”mixed” leucocytes by very gently tapping and swirling the Universal tubes. Using a syringe, without an attached needle pool all the cells into one tube then, using the same syringe, add 1ml of cell-free plasma containing ACD (from 6) and gently swirl to resuspend.

(11)   Reconstitute a vial of Ceretec with 5ml of technetium-99m generator eluate containing approximately 500 MBq (13.5mCi) of 99mTcO4 (using the procedure described above).

(12)    Immediately following reconstitution add 4 ml of the resulting technetium -99m exametazime solution to the “mixed” leucocytes in CFP (from 10)

(13)   Gently swirl to mix and incubate for 10 minutes at room temperature.

(14)   If required, immediately spot the chromatography strips for assessment of radiochemical purity of the technetium-99m exametazime, as instructed overleaf.

(15)   On completion of incubation carefully add 10ml of CFP containing sedimentation agent (from 9) to the cells, in order to stop labelling. Gently invert the cells to mix.

(16)   Centrifuge at 150g for 5 minutes

(17)   Remove and retain all the supernatant.
TIP It is critical that all the supernatant, which contains unbound technetium- 99m exametazime is removed at this stage. This can be best achieved using a syringe with a wide-bore [19G] needle.

(18)   Gently resuspend the technetium-99m labelled mixed leucocyte preparation in 5- 10m of CFP containing ACD from (6). Gently swirl to mix.

(19)   Measure the radioactivity in the cells and in the supernatant from (17). Calculate the labelling efficiency [LE], which is defined as the activity in the cells as a percentage of the sum of the activity in the cells and the activity in the supernatant.

TIP Labelling efficiency depends on the patient’s leucocyte count and will vary according to the volume of the initial blood sample. Using the volumes in (2), a LE of about 55% might be expected.

(20)   Without attaching a needle, carefully draw up the labelled cells into a plastic, non- heparinised syringe and close it with a sterile hub. Measure the radioactivity.
(21)     Labelled cells are now ready for re-injection. This should be performed without delay.

Note :

(a)    Acid-citrate-dextrose (ACD) should be made up as follows:
NIH Formula A. For 1 litre add 22g trisodium citrate, 8g citric acid, 22.4g dextrose and make up to 1 litre with Water for injections. The product should be manufactured under aseptic conditions. Commercial preparations of the product are also available. The Product should be stored under the conditions recommended by the manufacturer and should be used only up to the expiry date given by the manufacturer.

(b)    6% hydroxyethyl starch should be manufactured under aseptic conditions.
Commercial preparations of the product are available. The product should be stored under the conditions recommended by the manufacturer and should be used only up to the expiry date given by the manufacturer.

Quality control

Three potential radiochemical impurities may be present in the prepared exametazime injection. These are a secondary technetium 99mTc exametazime complex, free pertechnetate and reduced-hydrolysed-technetium-99m. A combination of two chromatographic systems is necessary for the determination of the radiochemical purity of the injection.

Test samples are applied by needle approximately 2.5cm from the bottom of two Glass Microfiber Chromatography Paper impregnated with Silicic Acid (GMCP-SA strips (2 cm (+ 2 mm) x 20cm). The strips are then immediately placed in prepared ascending chromatography development tanks, one containing butan-2-one and the other 0.9% aq.
Sodium chloride (1cm depth fresh solvent). After a 14cm elution the strips are removed, solvent fronts marked, the strips dried and the distribution of activity determined using suitable equipment.

Interpretation of chromatograms

System 1 (GMCP-SA: butan-2-one (methyl ethyl ketone))
99m
Secondary       Tc exametazime complex and reduced-hydrolysed-technetium remain at the origin.

Lipophilic 99mTc exametazime complex and pertechnetate migrate at Rf 0.8-1.0.

System 2 (GMCP-SA 0. 9% sodium chloride)
Lipophilic 99mTc exametazime complex, secondary       99m
Tc exametazime complex and reduced-hydrolysed-Tc remain at the origin.
Pertechnetate migrates at Rf 0.8-1.0.

(1)    Calculate the percentage of activity due to both secondary 99mTc exametazime complex and reduced-hydrolysed-technetium-99m from System 1 (A%).
Calculate the percentage of activity due to Pertechnetate from System 2 (B%).

(2)    The radiochemical purity (as percentage lipophilic 99mTc exametazime complex) is given by: 100-(A%+B%)where:
99m
A% represents the level of secondary              Tc exametazime complex plus reduced- hydrolysed technetium-99m

B% represents the level of pertechnetate.

A radiochemical purity of at least 80% may be expected provided the test samples have been taken and analysed within 30 minutes of reconstitution.