Technetium Tc 99m Exametazime (Systemic)


VA CLASSIFICATION
Primary: DX201

Commonly used brand name(s): Ceretec.

Another commonly used name for exametazime is
hexamethylpropyleneamine oxime (HM-PAO) .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Diagnostic aid, radioactive (cerebrovascular disease; inflammatory disease){37}

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Brain imaging, radionuclide—Technetium Tc 99m exametazime is indicated as a brain imaging agent in the detection of altered regional cerebral perfusion in stroke. {01} {08} {11} {22} {23}

Leukocytes, labeling of—Technetium Tc 99m exametazime is indicated for the labeling of autologous leukocytes. Technetium Tc 99m exametazime–labeled leukocytes are used for the following diagnostic studies:
Inflammatory lesions, intra-abdominal (diagnosis)1;
Bowel disease, inflammatory (diagnosis)—Indicated in scintigraphy to help locate intra-abdominal infection or inflammation and inflammatory bowel disease. {05} {06} {09} {10} {20} {22} {29} {33} {36} {37}

[Dementia, Alzheimer-type (diagnosis)]1—Technetium Tc 99m exametazime is used as a brain imaging agent to help identify patients with Alzheimer's disease. {04} {07}

[Epilepsy (diagnosis)]1—Technetium Tc 99m exametazime is used in the evaluation of epilepsy to help find the location of the epileptic focus. {15} {16} {29}

[Brain death (diagnosis)]1—Technetium Tc 99m exametazime is used to help confirm the diagnosis of brain death. {19} {22} {40}

1 Not included in Canadian product labeling.



Physical Properties

Nuclear data:



Radionuclide
(half-life)
Decay
constant
Mode
of
decay
Principal
photon
emissions
(keV)
Mean
number of
emissions/
disintegration
(³0.01)
Tc 99m
(6.0 hr)
0.1151 h -1
Isomeric
transition to
Tc 99
Gamma
(18)

0.062
Gamma
(140.5)
0.891


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Exametazime: 272.39 {03}

Mechanism of action/Effect:

Brain imaging—Technetium Tc 99m exametazime is a lipophilic complex able to cross the blood-brain barrier as well as penetrate cell membranes. The agent localizes in the brain as a function of regional cerebral perfusion. Its radionuclide emissions while localized in cerebral tissue permit external imaging of the cerebral distribution of the agent thus helping detect altered regional cerebral perfusion. Technetium Tc 99m exametazime is primarily extracted and trapped by cerebral gray matter and the basal ganglia during the first pass through the brain. It has been proposed that the retention in the brain of technetium Tc 99m exametazime results from in vivo conversion of the primary complex to a less lipophilic complex, which is unable to cross the blood-brain barrier. {01} {14} {17} {22}

Labeling of leukocytes—When incubated with leukocytes, which have been isolated from whole blood, the technetium Tc 99m exametazime complex, being lipid-soluble, penetrates the cell membrane of the leukocytes by passive diffusion. The lipophilic complex is then converted to a hydrophilic species, in a process possibly involving intracellular glutathione, thus trapping the technetium Tc 99m label within the cells (mostly neutrophils). The radioactive autologous leukocytes are subsequently reinjected to permit the detection of inflammatory lesions based on the normal physiological accumulation of leukocytes at such sites. {09} {22} {33} {37}

Distribution:

Brain imaging—Rapidly cleared from blood after intravenous injection; a maximum of 3.5 to 7% of administered activity localizes in the brain within one minute of injection. Up to 15% of this localized activity is eliminated from the brain within the next 2 minutes after injection, with little or no further loss of activity for the following 24 hours, except by physical decay of technetium Tc 99m. The activity that is not localized in the brain is widely distributed throughout the body, particularly in muscle and soft tissue. {01} {11} {12} {29} {33}

Diagnosis of inflammatory lesions—Technetium Tc 99m exametazime–labeled leukocytes tend to concentrate at sites of inflammation. However, there is an initial accumulation of radioactivity in the lungs, liver, spleen, blood pool, bone marrow, and the bladder. Activity is seen in the urine, occasionally in the gallbladder, and consistently in the colon from 4 hours on. Significant colonic activity remains 24 hours after injection. Also, normal areas visualized in earlier scans remain visible. {33} {35} {37}

Time to radioactivity visualization

Brain imaging—Dynamic imaging may be performed within the first 10 minutes post-injection. Static imaging may be performed 15 minutes after injection for up to 6 hours. {37}

Diagnosis of inflammatory lesions—Although some inflammatory lesions have been detected at 2 minutes post-injection, images taken at 30 minutes and/or 2 hours are recommended. Optimal planar images are obtained between 2 and 4 hours following administration. {33} {34} {37}

Radiation dosimetry:
{23}{27}{28}{33}

Estimated absorbed radiation dose
for Technetium Tc 99m Exametazime*
Organ
mGy/MBq
rad/mCi
Lacrimal glands
0.070
0.26
Gallbladder wall
0.051
0.19
Kidney
0.035
0.13
Thyroid
0.027
0.10
Upper large
intestine wall
0.021
0.079
Liver
0.015
0.054
Lower large
intestine wall
0.015
0.054
Bladder wall
2 hr void
0.013
0.047
4 hr void
0.019
0.070
Small intestine wall
0.012
0.044
Brain
0.0069
0.026
Eyes
0.0069
0.026
Ovaries
0.0063
0.023
Bone surfaces
0.0048
0.018
Red marrow
0.0034
0.013
Testes
0.0018
0.007
Total body
0.0036
0.013
Effective dose: 0.0092 mSv/MBq (0.034 rem/mCi) {28}.


Estimated absorbed radiation dose
for Technetium Tc 99m Exametazime–labeled leukocytes
Organ
mGy/MBq
rad/mCi
Spleen
0.15
0.56
Red marrow
0.022
0.082
Liver
0.02
0.074
Pancreas
0.014
0.052
Ovaries
0.0042
0.016
Uterus
0.0038
0.014
Testes
0.0017
0.0064
Effective dose: 0.017 mSv/MBq (0.063 rem/mCi) {28} {33}.
* For adults; intravenous injection. Data based on information from the Oak Ridge Associated Universities, Radiopharmaceutical Internal Dose Information Center. {23} {27}
 Data based on the International Commission on Radiological Protection (ICRP) Publication 53—Radiation dose to patients from radiopharmaceuticals. {28} {33}
 Data based on bladder voiding every 3.5 hours. {28} {33}

Elimination:


For technetium Tc 99m exametazime—


Within 48 hours—
        Fecal (about 50% of the administered activity via hepatobiliary excretion).
        Renal (about 40% of the injected administered activity). {01} {18} {22} {29} {33}




For technetium Tc 99m exametazime–labeled leukocytes {06} {35}
        Renal (about 15 to 30% of the injected administered activity in 24 hours).
        Fecal (about 6% of the administered activity in 48 hours).



Precautions to Consider

Carcinogenicity

Long-term animal studies to evaluate carcinogenic potential of technetium Tc 99m exametazime have not been performed. {01}

Mutagenicity

Studies in rats have not demonstrated mutagenic potential following intraperitoneal administration at doses of 70, 140, and 280 mg of exametazime per kg of body weight. {01}

Pregnancy/Reproduction

Pregnancy—
Tc 99m (as free pertechnetate) crosses the placenta. However, studies have not been done with technetium Tc 99m exametazime in humans. {01}

The possibility of pregnancy should be assessed in women of child-bearing potential. Clinical situations exist in which the benefit to the patient and fetus, based on information derived from radiopharmaceutical use, outweighs the risks from fetal exposure to radiation. In these situations, the physician should use discretion and reduce the administered activity of the radiopharmaceutical to the lowest possible amount. {24} {31}

Studies have not been done in animals.

FDA Pregnancy Category C. {23} {33}

Breast-feeding

Although it is not known whether technetium Tc 99m exametazime is distributed into breast milk, it is known that Tc 99m as free pertechnetate is distributed into breast milk. Based on the assumption that the Tc 99m in breast milk is in the form of pertechnetate, and based on the effective half-life of the radionuclide in breast milk, the daily volume of milk, a dose factor relating the radionuclide to its critical organ (thyroid) in the nursing infant, and the maximum permissible dose to that organ, a guideline has been proposed. According to this guideline, it has been calculated that nursing can be safely resumed when the concentration in breast milk reaches 30.3 × 10 -4 megabecquerels (8.2 × 10 -2 microcuries) per mL. This level of activity is probably reached, in the majority of patients, within 24 hours after administration of 740 megabecquerels (20 millicuries) of technetium Tc 99m–labeled radiopharmaceuticals. {05} However, the manufacturer recommends that formula feedings be substituted for breast-feeding for 60 hours. {33}

Pediatrics

Diagnostic studies performed to date in patients up to 18 years of age have not demonstrated pediatrics-specific problems that would limit the usefulness of technetium Tc 99m exametazime in children. However, there have been no specific studies evaluating the safety and efficacy of technetium Tc 99m exametazime in pediatric patients. When this radiopharmaceutical is used in children, the diagnostic benefit should be judged to outweigh the potential risk of radiation. {21} {24}

For technetium Tc 99m exametazime–labeled leukocytes—Technetium Tc 99m exametazime–labeled leukocytes may be preferred for use in children to indium In 111 oxyquinoline–labeled leukocytes or gallium citrate Ga 67 because of its lower radiation dose. {36} {37} {39}


Geriatrics


Appropriate studies on the relationship of age to the effects of technetium Tc 99m exametazime have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.

Drug interactions and/or related problems
See Diagnostic interference .

Diagnostic interference
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With results of technetium Tc 99m–labeled leukocyte studies

Due to other medications
Antibiotics    (long-term intravenous antibiotic therapy may result in a false-negative study {37} {38})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problem exists
Sensitivity to the radiopharmaceutical preparation


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Allergic reaction (fever; skin rash; swelling of face)
    
transient increase in blood pressure{33}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Radiopharmaceuticals (Diagnostic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Description of use
Action in the body: Concentration of radioactive exametazime in brain; concentration of technetium Tc 99m–labeled leukocytes at sites of infection

Retention of radioactivity in brain and sites of infection allows visualization

Small amount of radioactivity used in diagnosis; radiation received is low and considered safe

Before having this test
»   Conditions affecting use, especially:
Sensitivity to the radiopharmaceutical preparation

Pregnancy—Technetium Tc 99m (as free pertechnetate) crosses placenta; risk to fetus from radiation exposure as opposed to benefit derived from use should be considered





Breast-feeding—Not known if technetium Tc 99m exametazime is distributed into breast milk, but Tc 99m as free pertechnetate is distributed into breast milk; temporary discontinuation of nursing may be recommended to avoid any unnecessary absorbed radiation dose to the infant





Use in children—For brain imaging: Risk from radiation exposure as opposed to benefit derived from use should be considered


Preparation for this test
Special preparatory instructions may be given; patient should inquire in advance

Precautions after having this test
Increasing intake of fluids and voiding as often as possible after examination to minimize bladder exposure to radiation


Side/adverse effects
Signs of possible side effects, especially allergic reaction and transient increase in blood pressure


General Dosing Information
Radiopharmaceuticals are to be administered only by or under the supervision of physicians who have had extensive training in the safe use and handling of radioactive materials and who are authorized by the Nuclear Regulatory Commission (NRC) or the appropriate Agreement State agency, if required, or, outside the U.S., the appropriate authority.

Adequate hydration of the patient is recommended before and after examination to promote urinary excretion of radioactivity. Also, urination is recommended as often as possible after the examination to reduce bladder exposure to radiation. {01} {22}

For brain perfusion imaging
Dynamic imaging may be performed within the first 10 minutes after injection. Static imaging may be performed from 15 minutes up to 6 hours after injection. {01}

For labeling of leukocytes
White blood cells may be damaged by mechanical shearing forces; therefore, it is important to minimize the use of needles when transferring cells. If a syringe cannot be used by itself, wide-bore (19 gauge) needles should be used. When separating the mixed leukocytes from other blood cells, excessive centrifuge speed may damage the cells and increase platelet contamination. However, an adequate centrifuge speed will provide a compact button (pellet). {33} {37}

The manufacturer's package insert or other appropriate literature should be consulted for the specific method of labeling leukocytes. {37}

Safety considerations for handling this radiopharmaceutical
Improper handling of this radiopharmaceutical may cause radioactive contamination. Guidelines for handling radioactive material have been prepared by scientific, professional, state, federal, and international bodies and are available to the specially qualified and authorized users who have access to radiopharmaceuticals. {30}


Parenteral Dosage Forms

TECHNETIUM Tc 99m EXAMETAZIME INJECTION USP

Usual adult and adolescent administered activity
Brain imaging
Intravenous, 370 to 740 megabecquerels (10 to 20 millicuries). {01} {23}

Diagnosis of inflammatory lesions
Intravenous, 0.259 to 0.925 gigabecquerels (7 to 25 millicuries) of technetium Tc 99m exametazime–labeled leukocytes. {33}


Usual pediatric administered activity
Brain imaging
Intravenous, 5 to 10 megabecquerels (0.14 to 0.28 millicuries) per kg of body weight with a minimum total dosage of 185 megabecquerels (5 millicuries). {26} {29}

Diagnosis of inflammatory lesions
Dosage must be individualized by physician. {36}


Usual geriatric administered activity
See Usual adult and adolescent administered activity.

Strength(s) usually available
U.S.—


0.5 mg exametazime, 7.6 mcg (0.0076 mg) stannous chloride dihydrate, and 4.5 mg sodium chloride, in lyophilized form under nitrogen atmosphere, per single-dose reaction vial (Rx) [Ceretec{01}{23}]

Note: In addition, the kit contains 1-mL vials of 1% methylene blue injection and 4.5-mL vials of 0.003 M monobasic sodium phosphate and dibasic sodium phosphate in 0.9% sodium chloride injection. {33} {37}


Canada—


0.5 mg exametazime, 7.6 mcg (0.0076 mg) stannous chloride dihydrate, and 4.5 mg sodium chloride, in lyophilized form under nitrogen atmosphere, per single-dose reaction vial (Rx) [Ceretec{21}{22}]

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F), unless otherwise specified by manufacturer. Protect from freezing. {33}

Note: Prior to labeling, kit must be stored between 15 and 25 °C (59 and 77 °F). {33}


Preparation of dosage form:
To prepare injection, an oxidant-free sodium pertechnetate Tc 99m solution is used. Freshly eluted technetium Tc 99m generator eluate must be used for reconstitution to assure the highest radiochemical purity. It is recommended that only eluate from a technetium Tc 99m generator that was previously eluted within 24 hours should be used. Generator eluate more than 2 hours old should not be used. Preservative-free, nonbacteriostatic sodium chloride injection must be used as the diluent for sodium pertechnetate Tc 99m. Bacteriostatic sodium chloride should not be used because it will increase the oxidation products and adversely affect the biological distribution of technetium Tc 99m exametazime. Methylene blue injection may be used to form a stabilizing solution. See manufacturer's package insert for full preparation instructions. {01} {22}

Note: Methylene blue must not be used as a stabilizer in the preparation of the technetium Tc 99m exametazime injection to be used for labeling leukocytes. {33} {37}


Stability:
Without methylene blue stabilizer—Injection must be administered within 30 minutes after preparation since progressive conversion to a less lipophilic complex unable to cross the blood-brain barrier may exceed acceptable limits after this time period. {01} {29} {33}

With methylene blue stabilizer—Injection may be administered within 4 hours after time of reconstitution. {33}

Incompatibilities:
If oxidants such as peroxides and hypochlorites are present in the sodium pertechnetate Tc 99m used for labeling, the final preparation may be adversely affected and should be discarded.

Note: Caution—Radioactive material.




Revised: 01/11/1996



References
  1. Ceretec package insert (Medi-Physics—US), Rev 8/89.
  1. Chilton HM, Witcofski RL. Nuclear Pharmacy—An introduction to the clinical application of radiopharmaceuticals. Philadelphia: Lea & Febiger, 1986: 99-101.
  1. Fleeger CA, editor. USAN 1993. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1992: 260.
  1. Smith FW, Besson JA, Gemmel HG, et al. The use of technetium 99m HM-PAO in the assessment of patients with dementia and other neuropsychiatric conditions. J Cereb Blood Flow Metab 1988 Dec; 8(6): S116-S122.
  1. Scholmerich J, Schmidt E, Schumichen C, et al. Scintigraphic assessment of bowel involvement and disease activity in Crohn's disease using technetium Tc 99m hexamethyl propylene amine oxine as leukocyte label. Gastroenterology 1988 Nov; 95(5): 1287-93.
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