CERETEC^™
Kit for the Preparation of Technetium Tc99m Exametazime Injection

The Ceretec kit is supplied as five packs of three vials for use in the preparation of a technetium Tc99m exametazime intravenous injection as a diagnostic radiopharmaceutical for use as an adjunct in the detection of altered regional cerebral perfusion and for the radiolabeling of autologous leukocytes. Each vial of Ceretec contains a pre-dispensed sterile, non-pyrogenic, lyophilized mixture of 0.5 mg exametazime [(RR,SS)-4.8-diaza-3,6,6,9-tetramethylundecane-2, 10-dione bisoxime], 7.6 µg stannous chloride dihydrate (minimum stannous tin 0.6 µg; maximum total stannous and stannic tin 4.0 µg per vial) and 4.5 mg sodium chloride, sealed under nitrogen atmosphere with a rubber closure. The product contains no antimicrobial preservative.

In addition, each package contains five 1 mL vials of Methylene Blue Injection USP 1% containing 10 mg methylene blue USP in Water for Injection q.s. pH adjusted with sodium hydroxide and/or hydrochloric acid, when necessary. Methylene Blue Injection USP is a sterile, non-pyrogenic solution of phenothiazin-5-ium,3,7-bis (dimethylamino)-chloride, trihydrate. Each package also contains five 4.5 mL vials of 0.003 M Monobasic Sodium Phosphate USP and Dibasic Sodium Phosphate USP in 0.9% Sodium Chloride Injection USP. The solution is sterile and non-pyrogenic. Each mL contains 0.276 mg monobasic sodium phosphate monohydrate, 0.142 mg dibasic sodium phosphate anhydrous and 9 mg sodium chloride in Water for Injection q.s. The total calculated osmolarity of the 0.003 M Monobasic Sodium Phosphate USP and Dibasic Sodium Phosphate USP in 0.9% Sodium Chloride Injection USP is 317 mOsmol/L. Each mL provides 0.285 mg (3mM) of phosphate, 0.157 mEq of sodium and 0.154 mEq of chloride. When used according to the preparation instructions (see DOSAGE AND ADMINISTRATION), Methylene Blue Sodium Phosphates/Sodium Chloride mixture acts as a stabilizer.

Prior to publication of the USAN, exametazime was formerly known as hexamethylpropylene amine oxime (HM-PAO). The name HM-PAO appears in many publications.

The structural formula of exametazime is:

When sterile pyrogen-free sodium pertechnetate Tc99m in isotonic saline is added to the vial of Ceretec, a Tc99m complex of exametazime is formed.

Administration is by intravenous injection for diagnostic use.

Technetium Tc99m decays by isomeric transition with a physical half-life of 6.03 hours.⁽¹⁾ Photons that are useful for imaging studies are uled in Table 1.

The specific gamma ray constant for technetium Tc99m is 206 microCoulomb kg^-1/37 MBq-h, (0.8 R/millicurie-h) at 1 cm. The first half-value thickness of lead (Pb) for technetium Tc99m is 0.2 mm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 2. For example, the use of a 2.7 mm thickness of Pb will decrease the external radiation exposure by a factor of 1,000.

To correct for physical decay of this radionuclide, the fractions that remain at selected intervals relative to the time of calibration are shown in Table 3.

When technetium Tc99m pertechnetate is added to exametazime in the presence of stannous reductant, a lipophilic technetium Tc99m complex is formed. This lipophilic complex is the active moiety. It converts at approximately 12%/hour to less lipophilic species. When the secondary complex is separated from the lipophilic species, it is unable to cross the blood-brain-barrier. The useful life of the reconstituted agent is limited to 30 minutes. The in vitro addition of methylene blue to the Tc99m-exametazime will stabilize the complex for 4-6 hours. Methylene blue may be added to Tc99m for cerebral imaging. Methylene blue should not be used in the preparation of Tc99m-exametazime labeled leukocytes. (See section on Preparation and Handling).

Studies in normal volunteers have shown that the technetium Tc99m complex of the RR,SS(d,l) diastereoisomer of exametazime is rapidly cleared from the blood after intravenous injection. Uptake in the brain reaches a maximum of 3.5-7.0% of the injected dose within one minute of injection. Up to 15% of the activity is eliminated from the brain by 2 minutes post injection, after which little activity is lost for the following 24 hours except by physical decay of technetium Tc99m. The activity not associated with the brain is widely distributed throughout the body, particularly in muscle and soft tissue. About 30% of the injected dose is found in the gastrointestinal tract immediately after injection and about 50% of this is excreted through the intestinal tract over 48 hours. Also, about 40% of the injected dose is excreted through the kidneys and urine over the 48 hours after injection.

The use of methylene blue for stabilization prior to injection does not appear to affect the pharmacokinetic handling or distribution of Tc99m exametazime.

The lipophilic Tc99m exametazime complex (that is not stabilized by methylene blue) is taken up by leukocytes, and selectively retained in neutrophils. Label elution rate is up to 10% in the first hour.

Tc99m-labeled leukocyte: Based upon in vivo recovery and very low lung and liver uptake, the labeled leukocytes are still functional. Following reinjection of the Tc99m labeled leukocytes the circulating granulocyte activity as a percentage of labeled granulocyte activity at 40 minutes after injection gave a mean of 37% (range 10-47%).

During the first hour following injection of Tc99m labeled leukocytes, activity is seen in the lungs, liver, spleen, blood pool, bone marrow and the bladder. The kidneys (parenchyma and/or renal pelvis) and gall bladder may also be visualized. Over the first 1-6 hours, the Tc99m is visualized in the bowel. At 24 hours post-injection substantial colonic activity is seen. The normal areas visualized in earlier scans are still visible.

Two clinical trials were performed in a total of 88 patients who had suspected intra-abdominal infection or inflammation. Subjects received both Tc99m labeled leukocytes and In111-labeled leukocytes. Images were obtained at 2 and 30 minutes and at 2 and 4 hours and 24 hours. In two other clinical trials, in a total of 127 patients with suspected abdominal inflammation or infection received Tc99m labeled leukocytes. Imaging was at 24 hours in one study and at 1, 3 and 24 hours in the other. In all four studies images were blindly evaluated and the findings were confirmed by surgery, biopsy or other clinical data.

Based on the above 4 studies, between 2 to 4 hours Tc99m labeled leukocytes had 95-100% sensitivity and 62-85% specificity with similar numbers of false positive and false negative findings. The value of the 24 hour Tc99m labeled leukocyte images is inconsistent. In all studies the false positive and false negatives relate to the bowel background, the location of the site of infection/inflammation and whether or not it is contiguous with the bowel. The 24 hour films should be interpreted with great caution because of a high bowel background; false negatives were noted in both Tc99m and In111 labeled leukocytes.

Other studies suggest that the interpretation of the images could be affected by the presence of tumors, infarction and peritonitis, etc. Liver abscess may be missed because of the bowel background. Caution should be exercised in making the final diagnosis.

Technetium Tc99m exametazime scintigraphy (with or without methylene blue stabilization) may be useful as an adjunct in the detection of altered regional cerebral perfusion in stroke.

Tc99m exametazime without methylene blue stabilization is indicated for leukocyte labeled scintigraphy as an adjunct in the localization of intra-abdominal infection and inflammatory bowel disease.

None known.

As with any injected product, acute hypersensitivity or allergic reactions are possible. Limited reports have been received of hypersensitivity reactions following administration of Tc99m labeled leukocytes prepared using Tc99m exametazime. However, the materials used in leukocyte cell separation may cause hypersensitivity reactions. It is essential that cells are washed free of sedimentation agents before they are reinjected into the patient.

In case of side effects following administration of radio-pharmaceuticals, users should ensure the availability of appropriate medical treatment at the time of administration of any radiopharmaceutical to the patient.

A thorough knowledge of the normal distribution of intravenously administered technetium Tc99m exametazime injection is essential in order to interpret pathologic studies accurately. Caution should be exercised in making the final diagnosis. Results can be affected by the presence of tumor, infarction, peritonitis, non-gastrointestinal or bony sites of inflammatory cell collections.

The spans of the Ceretec vial are not radioactive. After the sodium pertechnetate Tc99m is added, the product is radioactive and adequate shielding of the final preparation must be maintained. The spans of the Ceretec vial are intended only for use in preparation of technetium Tc99m exametazime injection and are NOT to be administered directly to the patient.

The spans 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.

Radiopharmaceuticals should be used only by or under the control of physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides.

To minimize radiation dose to the bladder, the patient should be encouraged to void when the examination is completed and as often thereafter as possible. Adequate hydration should be encouraged to permit frequent voiding.

Long term animal studies have not been performed to evaluate carcinogenic potential or whether exametazime affects fertility in males or females. When evaluated in the Ames test, exametazime increased the apparent rate of gene mutation in the TA100 strain of S. typhimurium. Exametazime did not cause chromosomal aberrations in vitro (Chinese Hamster Ovary cells) or in vivo (rat bone marrow).

Animal reproduction studies have not been conducted with Tc99m exametazime. It is also not known whether Tc99m exametazime can cause fetal harm when administered to a pregnant woman or if it can affect reproductive capacity. Therefore, Tc99m exametazime should not be administered to a pregnant woman unless the potential benefit justifies the potential risk to the fetus.

Technetium Tc99m is excreted in human milk during lactation. It is not known whether exametazime is excreted in human milk. Therefore, formula feedings should be substituted for breast feeding for 60 hours.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of Ceretec™ did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Rash with generalized erythema, facial edema and fever has been reported in less than 1% of patients. A transient increase in blood pressure was seen in 8% of patients.

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. Do not use methylene blue in the preparation of the Tc99m labeled leukocytes (See preparation and handling section).

The recommended dose range for i.v. administration, of reconstituted sodium pertechnetate Tc99m exametazime (with or without methylene blue) 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.

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 spans 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 Immunodeficiency 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.

• 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. For brain imaging when using stabilizing protocol, generator eluate more than 30 minutes old should not be used. For the highest radiochemical purity reconstitute with freshly eluted technetium Tc99m generator eluate. For white blood cell labeling, generator elute more than 2 hours 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 for stabilized Ceretec more than 4 hours after the time of reconstitution. Do not use the final radiopharmaceutical preparation for unstabilized Ceretec more than 30 minutes after the time of reconstitution. Discard any unused material.

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.

• 1)Quality control kit which includes all necessary components (available from BIODEX Medical Systems Inc./ Phone # 516-924-9000 – Cat. #151-660).
• 2) Individual supplies:
  Gelman ITLC/SG strips 6 cm × 0.7 cm (available from BIODEX Medical Systems Inc./Phone # 516-924-9000 – Black Strip)
  Whatman strips 6 cm × 0.7 cm (available from BIODEX Medical Systems Inc./Phone # 516-924-9000 – Red Strip)
  MEK (methyl ethyl ketone [butanone]) (Aldrich Cat. #27069-5, 99.9 + % HPLC Grade)
  0.9% aqueous sodium chloride (non-bacteriostatic)
  50% aqueous acetonitrile (Aldrich Cat. #27071-7, 99.9 + % HPLC Grade)
  Dilute with non-bacteriostatic Water for Injection
  Glass test tubes (12 × 75 mm)
  1 mL syringes with 25 gauge needles
• 3) Suitable counting equipment.

• 1)Prepare three chromatography tubes containing 0.2-0.3 mL of fresh MEK, 0.9% sodium chloride and 50% acetonitrile, respectively. Identify the solvent in each tube.
• 2)Prepare two ITLC/SG (black) strips and one Whatman paper (red) strip. Each is marked by the manufacturer 1.0 cm from the bottom as the point of origin.
• 3)Reconstitute a Ceretec vial according to this insert.
• 4)Apply at least 5 µL samples of Ceretec to the origin of the three strips within 15 minutes of reconstitution. Immediately place one ITLC/SG (black) strip into the MEK tube, the second ITLC/SG (black) strip into the saline tube and the paper (red) strip into the 50% acetonitrile tube. Make sure strips are not adhering to the side of the test tube.
• 5)The ITLC/SG MEK (black) strip takes approximately 45 seconds to run. When the eluate has reached the solvent front remove the strip from the tube with forceps and immediately cut 1.0 cm above the origin.
• 6)The ITLC/SG saline (black) strip takes approximately 45 seconds to run. When the eluate has reached the solvent front remove the strip from the tube with forceps and immediately cut 2.5 cm above the origin.
• 7)The Whatman paper CH₃CN (red) 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 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.

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 uled 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.

The kit comprises five individual vials of sterile, non-pyrogenic, freeze-dried mixture of exametazime, stannous chloride dihydrate and sodium chloride, ten radiation labels, six sterile alcohol swabs, five radiochemical purity worksheets, five labeling efficiency worksheets, one package insert, five individual vials of Methylene Blue Injection USP 1%, five individual vials of 0.003 M Monobasic Sodium Phosphate USP and Dibasic Sodium Phosphate USP in 0.9% Sodium Chloride Injection USP and fifteen 0.45 µM syringe filters.

NDC 17156-023-05

Store the kit at 15°-25°C (59°-77°F).

Store the formulated drug at 20°-25°C (68°-77°F) using appropriate radiation shielding. Do not freeze.

This reagent kit is approved for use by persons licensed by the Illinois Emergency Management Agency pursuant to 32 Ill. Code Adm. Section, Section 330.260(a) and 335.4010 or under equivalent licenses of the U.S. Nuclear Regulatory Commission, or an Agreement State.