CERETEC

CERETEC- exametazime injection, powder, lyophilized, for solution
GE Healthcare, Medi-Physics, Inc.

Diagnostic Radiopharmaceutical

For intravenous use only

DESCRIPTION

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:

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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.

Physical Characteristics

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

Table 1. Principal Radiation Emission Data-technetium Tc99m
Radiation Mean %/ Disintegration Mean Energy (keV)
(1) Dillman, L.T. and Von der Lage, F.C. Radionuclide decay schemes and nuclear parameters for use in radiation-dose estimation. MIRD Phamphlet No. 10, p. 62, 1975.
Gamma 2 87.87 140.5

External radiation

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.

Table 2. Radiation Attenuation by Lead Shielding
Shield Thickness (Pb) mm Coefficient of Attenuation
0.2 0.5
0.95 10–1
1.8 10–2
2.7 10–3
3.6 10–4
4.5 10–5

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.

Table 3. Physical Decay Chart – Tc99m half-life 6.03 hours
Hours Fraction Remaining Hours Fraction Remaining
*
Calibration time (time of preparation)
0* 1.000 7 0.447
1 0.891 8 0.399
2 0.795 9 0.355
3 0.708 10 0.317
4 0.631 11 0.282
5 0.563 12 0.252
6 0.502 24 0.063

CLINICAL PHARMACOLOGY

General

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).

Pharmacokinetics

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.

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