CERETEC Powder for solution for injection Ref.[11136] Active ingredients: Technetium ⁹⁹ᵐTc exametazime

Tc99m labeled leukocytes for adjunctive localization of intra-abdominal infection or inflammation.

The normal adult (70 kg) dose is 0.259-0.925 GBq (7-25 mCi) as Tc99m labeled leukocytes by intravenous injection. Optimal planar imaging is between 2-4 hours.

Cerebral Scintigraphy

The recommended dose range for i.v. administration, of reconstituted sodium pertechnetate Tc99m exametazime in the average adult (70 kg) is 370-740 MBq (10-20 mCi).

Dynamic imaging may be performed between 0 to 10 minutes following injection. Static imaging may be performed from 15 minutes up to 6 hours after injection.

Instructions for preparation and use

General preparation precautions

The technetium Tc99m labeling reaction involved in preparing technetium Tc99m exametazime injection depends on maintaining tin in the divalent (reduced) state. Any oxidant present in the sodium pertechnetate Tc99m employed may adversely affect the quality of the preparation. Sodium pertechnetate Tc99m containing oxidants should not be used for the preparation of the labeled product. To meet the last requirement, a generator must be eluted within 24 hours prior to obtaining any elute for reconstitution with the Ceretec kit.

Sodium Chloride Injection, USP must be used as the diluent. Do not use bacteriostatic sodium chloride as a diluent for sodium pertechnetate Tc99m injection because it will increase the oxidation products and adversely affect the biological distribution of Ceretec.

The contents of the Ceretec vial are sterile and pyrogen free. The vial contains no bacteriostatic preservative. It is essential that the user follow the directions carefully and adhere to strict aseptic procedures during preparation of the radiopharmaceutical.

Technetium Tc99m exametazime injection, like other radioactive drugs, must be handled with care and appropriate safety measures should be used to minimize radiation exposure to clinical personnel. Care should also be taken to minimize radiation exposure to the patient consistent with proper patient management.

Care should be taken when handling blood specimens to be labeled using this radiopharmaceutical. Even if the subject has been tested, no method can offer complete assurance that Hepatitis B Virus, Human Immuno-deficiency Virus (HIV) or other infectious agents are absent. All human blood samples should be considered potentially infectious. Precautions for handling are as those for handling radioactive materials.

Procedure for the Preparation of Technetium Tc99m Exametazime Injection

Note: Sterile technique must be used throughout. The user should wear waterproof gloves during the handling and administration procedure.

1. Place one of the vials in a suitable shielding container and sanitize the rubber septum with an isopropyl alcohol swab.
2. Using a 10 mL syringe, inject into the shielded vial 5 mL of sterile eluate from a technetium Tc99m generator (see cautionary notes 1-3). Before withdrawing the syringe from the vial, withdraw 5 mL of gas from the space above the solution to normalize the pressure in the vial. Gently invert 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. The patient dose should be measured in a suitable radioactivity calibration system immediately prior to administration.
4. Complete the label provided and attach to the vial shield. The technetium Tc99m exametazime injection is ready for quality control.
5. Maintain adequate shielding of the radioactive preparation.
6. Do not use the preparation more than 30 minutes after time of formulation. Discard any unused material.
7. Visually inspect the reconstituted material at a safe distance behind lead glass, and do not use if there is evidence of foreign matter.
8. The injection may be prepared for use in cerebral scintigraphy or for use in the preparation of Tc99m labeled white blood cells (WBCs).
9. The pH of the prepared injection is 9.0-9.8.
10. Also see section on Cautionary Notes for all Preparations.

Procedure for Radiolabeling of Autologous Leukocytes with Technetium Tc99m Exametazime Injection

Note: Sterile technique must be used throughout. The user should wear waterproof gloves during the handling and administration procedure.

1. Prepare a 60 mL syringe containing 10 mL acid citrate dextrose solution.
2. Using aseptic venipuncture technique and the prepared syringe (from Step 1) fitted with a 19 or 20 gauge needle, withdraw approximately 40 mL whole blood from the patient. (Blood withdrawal should be smooth and slow so as not to produce bubbles or foaming). Cap syringe after withdrawing blood.
3. Gently mix the contents of the syringe.
4. Clamp the syringe barrel to the ring stand in an upright (needle side up) position and tilt the syringe 10-20 degrees from its position perpendicular to the bench.
5. Allow the red cells to sediment 30-60 minutes, depending upon when the supernatant [leukocyte rich plasma (LRP)] looks clear of red blood cells.
6. Replace the capped needle with a winged infusion set.
7. Collect the plasma LRP into a centrifuge tube marked WBC by expressing the LRP through the infusion set tubing assuring the red cells do not enter the container.
8. Immediately centrifuge the capped WBC tube at 400-450 g for 5 minutes.
9. Transfer the supernatant to the leukocyte poor plasma (LPP) tube allowing enough supernatant to cover the white cell button.

(Note: the button often contains a small number of red cells and may appear red.) Reserve LPP for later use (steps 12, 16, 19).

1. Wash the white cell button with approximately 5.0 mL Sodium Chloride Injection, USP (0.9%). Cap the tube and resuspend the button by gently swirling.
2. Centrifuge the capped WBC tube at 150 g for 8 minutes and discard all but 0.5-1.0 mL of the supernate to cover the cells.
3. Add 1.0 mL of LPP to the white cell button and resuspend the cells by gentle swirling.
4. Reconstitute a vial of Ceretec with approximately 30 mCi of Tc99m pertechnetate in 5.0 mL Sodium Chloride (0.9%) Injection, according to the procedure outlined below. Generator eluate more than 2 hours old should not be used. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration.
5. Add the Tc99m Ceretec to the WBC tube. Swirl gently to mix.
6. Set a lab timer for 15 minutes and allow the white cells to incubate. Swirl periodically during the incubation.
7. After incubation, withdraw about 10 mL of the LPP and add to the white cell suspension in the WBC tube.
8. Cap the WBC tube, gently swirl, and then centrifuge at 450 g for 5 minutes.
9. Decant the supernatant in the WBC tube into the wash tube and leave the labeled white cells in the WBC tube.
10. Add approximately 5 mL of LPP to the WBC tube. Resuspend the cells by gentle swirling.
11. When the cells are in suspension, withdraw the cells into a syringe. Cap the syringe and assay the amount of radioactivity in a dose calibrator.
12. Place the syringe in a lead shielded container.
13. Administer the Tc99m labeled leukocyte suspension using a 19G needle as soon as possible after labeling.
14. Also see section of Cautionary Notes for all Preparations.

Cautionary Notes for all Preparations

1. 0.37 GBq up to 2.00 GBq (10 mCi up to 54 mCi) technetium Tc99m may be added to the vial. Before reconstitution the technetium Tc99m generator eluate may be adjusted to the correct radioactive concentration to a volume of 5 mL by dilution with preservative-free, non-bacteriostatic saline for injection.
2. Use only eluate from a technetium Tc99m generator which was previously eluted within 24 hours. Generator eluate more than 2 hours old should not be used. For the highest radiochemical purity reconstitute with freshly eluted technetium Tc99m generator eluate. When reconstituting a vial of Ceretec with 31 to 54 mCi, generator eluate more than 30 minutes old should not be used.
3. Radiochemical purity testing must be performed prior to patient administration. A radiochemical purity greater than 80% is necessary for product acceptance.
4. Do not use the final radiopharmaceutical preparation more than 30 minutes after the time of reconstitution. Discard any unused material.

Quality Control

Radiochemical purity determination must be performed before administration to the patient. Three potential radiochemical impurities may be present in the prepared injection of the lipophilic technetium Tc99m exametazime complex.

These are a secondary technetium Tc99m exametazime complex, free pertechnetate, and reduced-hydrolyzed-technetium Tc99m. A combination of 3 chromatographic systems is necessary for the complete definition of the radiochemical composition of the injection.

The following protocol has been designed to enable analysis of the radiochemical purity of Ceretec (99mTc-exametazime). It should be started within 2 minutes of reconstitution. The entire procedure takes approximately 15 minutes.

Equipment and Eluents

1. Quality control kit which includes all necessary components
2. Individual supplies:
   SA ITLC strips 20 cm × 2.0 cm
   Whatman No. 1 strips 6 cm × 0.7 cm
   MEK (methyl ethyl ketone [butanone]) (99.9 + % HPLC Grade)
   0.9% aqueous sodium chloride (non-bacteriostatic)
   50% aqueous acetonitrile (99.9 + % HPLC Grade)
   Dilute with non-bacteriostatic Water for Injection
   Glass test tubes (12 × 75 mm)
   Glass measuring cylinders (100ml) with covers
   1 mL syringes with 25 gauge needles
3. Suitable counting equipment.

Method

1. Prepare one chromatography tube containing 0.2-0.3 mL of 50% acetonitrile. Prepare two 100 ml cylinders each containing a 1 cm depth of fresh MEK and 0.9% sodium chloride, respectively. Identify the solvent in each cylinder.
2. Prepare two SA ITLC strips and one Whatman No. 1 paper strip. Mark the Whatman strip 1.0 cm from the bottom as the point of origin. Mark the SA ITLC strips 2.5cm from the bottom as the point of origin. Mark both the SA ITLC strips at 14 cm above the origin (solvent front).
3. Reconstitute a Ceretec vial according to this insert.
4. Apply at least 5 µL samples of Ceretec to the origin of the 3 strips within 15 minutes of reconstitution. Immediately place one SA ITLC strip into the MEK tank, the second SA ITLC strip into the saline tank and the Whatman No. 1 paper strip into the 50% acetonitrile tube. Make sure strips are not adhering to the sides of the container.
5. The SA ITLC MEK strip takes approximately 15 minutes to run. When the eluate has reached the solvent front mark remove the strip from the tube with forceps and immediately cut 1.0 cm above the origin.
6. The SA ITLC saline strip takes approximately 15 minutes to run. When the eluate has reached the solvent front mark remove the strip from the tube with forceps and immediately cut 2.5 cm above the origin.
7. The Whatman No. 1 paper CH₃CN strip takes approximately 100 seconds to run. When the eluate has reached the solvent front remove the strip from the tube with forceps and immediately cut 0.5 cm above the origin.
8. Count the separate sections of each strip to determine the activity distribution. Make sure proper counting geometry is maintained attempting to reduce any interference from equipment dead time.
9. Determine:

% bottom of saline strip – % bottom of MEK strip
(= % lipophilic exametazime complex)
% top of saline strip (= % pertechnetate)
% bottom of Whatman No. 1 paper strip (= % reduced-hydrolyzed-Tc)
A radiochemical purity of >80% may be expected provided the measurement has been carried out within 4 hours of reconstitution for stabilized Ceretec and 30 minutes for Ceretec used for WBC labeling.

Interpretation of Chromatogram

System 1 (SA ITLC: MEK [butanone]):

Secondary Tc exametazime complex and reduced-hydrolyzed-Tc remain at the origin.

Lipophilic Tc exametazime complex and pertechnetate migrate at R_f 0.8-1.0.

System 2 (SA ITLC: 0.9% sodium chloride):

Lipophilic-Tc exametazime complex, secondary Tc exametazime complex and reduced-hydrolyzed-Tc remain at the origin. Pertechnetate migrates at R_f 0.8-1.0.

System 3 (Whatman No. 1 1: 50% aqueous acetonitrile):

Reduced-hydrolyzed-Tc remains at the origin. Lipophilic Tc exametazime complex, secondary Tc exametazime complex and pertechnetate migrate at R_f 0.8-1.0.

RADIATION DOSIMETRY

Based on human data, the absorbed radiation doses to an average human adult (70 kg) from an intravenous injection of this product are estimated below. The values are listed as µGy/MBq, rads/mCi with urination every 2 hours. Bladder wall dose is 19 µGy/MBq, 0.07 rads/mCi with 4 hour urination and 89 µGy/MBq, 0.33 rads/mCi with no urination.

Table 4. Estimated Absorbed Radiation Dose* for Cerebral Scintigraphy:

Table 5. In vivo Localization of Tc99m Labeled Leukocytes:

Effective Dose Equivalent (EDE) 3.4 mSv/200 MBq.

^* International Commission on Radiological Protection, “Radiation Dose to Patients from Radiopharmaceuticals”, ICRP 53, 1988.

Store the kit at 15°-25°C (59°-77°F).

Store the formulated drug for up to 30 minutes at 20°-25°C (68°-77°F) using appropriate radiation shielding.