Technetium Tc 99m Bicisate (Systemic)


VA CLASSIFICATION
Primary: DX201

Commonly used brand name(s): Neurolite.

Another commonly used name for bicisate is
ethyl cysteinate dimer (ECD) .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Diagnostic aid, radioactive (cerebrovascular disease)—

Indications

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

Accepted

Brain imaging, radionuclide—Single-photon emission computed tomography (SPECT) {28} using technetium Tc 99m bicisate is indicated as an adjunct to conventional computed tomography (CT) or magnetic resonance imaging (MRI) in the localization of stroke in patients in whom stroke has already been diagnosed. {01} {07} {08} {09} {13} {15} {20} {21} {22} {31} However, [technetium Tc 99m bicisate is also used in the evaluation and localization of altered regional cerebral perfusion{05}{10}{12}{14}{15}{16}{17}{19}{24}{25}{27} associated with functional impairment in patients with neurological disorders not limited to stroke{29}{30} , but including such disorders as dementia{15}{29}{32}{33} , head trauma{29} , and epilepsy{29}{34}{35}] .


Physical Properties

Nuclear data {01}:



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

Mechanism of action/Effect:

Brain imaging—Technetium Tc 99m bicisate is a lipophilic complex with high first-pass extraction fraction and deposition and retention in the brain in proportion to cerebral blood flow (perfusion). {07} {09} {10} {11} {19} {25} {28} Its radionuclide emissions permit external imaging of the cerebral distribution of the agent, thus allowing the detection of altered regional cerebral perfusion. The retention in the brain of technetium Tc 99m bicisate results from in vivo metabolism (deesterification) of the primary complex to polar, less diffusable compounds (mono- and di-acids). {01} {07} {10} {18} {25} {28}

Distribution:

High initial cerebral uptake with rapid blood clearance after intravenous injection (less than 10% of the administered activity remains in the blood after 5 minutes) {09} {12} {15} {19} {25}. Approximately 5 to 8% of administered activity localizes in the brain within 5 minutes after injection and exhibits little change for one hour after injection. Brain washout is approximately 20% between 5 and 60 minutes after injection and approximately 10% per hour thereafter. {09} {10} {11} {15} {19} {25} {26} {28}

Time to radioactivity visualization:

10 minutes to 6 hours after injection. Optimal images may be obtained 30 to 60 minutes after administration to allow washout from facial muscles and salivary glands and thereby increase brain-to-soft-tissue ratios. {01} {25} {28}

Radiation dosimetry:
{05}

Organ
Estimated absorbed radiation dose*
With 2-hour
void
With 4.8-hour
void
mGy/
MBq
rad/
mCi
mGy/
MBq
rad/
mCi
Urinary bladder
wall

0.03

0.11

0.073

0.27
Gallbladder wall
0.025
0.091
0.025
0.091
Large intestine
wall, upper

0.016

0.061

0.017

0.063
Large intestine
wall, lower

0.013

0.047

0.015

0.055
Small intestine
0.0094
0.035
0.01
0.038
Kidneys
0.0073
0.027
0.0074
0.027
Uterus
0.0063
0.023
0.011
0.041
Brain
0.0055
0.02
0.0055
0.02
Ovaries
0.0054
0.022
0.008
0.03
Liver
0.0053
0.02
0.0054
0.02
Thyroid
0.0035
0.013
0.0035
0.013
Bone surfaces
0.0034
0.013
0.0038
0.014
Adrenals
0.0025
0.009
0.0025
0.009
Pancreas
0.003
0.011
0.003
0.011
Red marrow
0.0024
0.009
0.0027
0.01
Stomach
0.0024
0.009
0.0025
0.0093
Testes
0.0022
0.008
0.0036
0.013
Muscle
0.002
0.007
0.0024
0.009
Spleen
0.002
0.0073
0.002
0.0073
Lungs
0.002
0.008
0.002
0.008
Heart wall
0.0018
0.0067
0.0018
0.0067
Skin
0.001
0.0037
0.0012
0.0043
Thymus
0.0013
0.0047
0.0013
0.0047
Breast
0.00094
0.0037
0.00094
0.0037
Total body
0.0024
0.009
0.0029
0.011


Radionuclide
Effective dose Technetium Tc 99m bicisate
With 2-hour
void
With 4.8-hour
void
mSv/
MBq
rem/
mCi
mSv/
MBq
rem/
mCi
Tc 99m
0.0095
0.035
0.013
0.048
* For adults; intravenous injection. Data based on information from the Oak Ridge Associated Universities, Radiopharmaceutical Internal Dose Information Center. {05}
 Calculated according to the method of the International Commission on Radiological Protection (ICRP) publication 60. {05}

Elimination:
    Renal—About 50% of the administered activity is excreted as metabolites within 2 hours, and about 74% within 24 hours. {01} {11} {18} {19} {28}
    Fecal—About 12% of the administered activity is excreted after 48 hours. {01} {28}


Precautions to Consider

Carcinogenicity

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

Pregnancy/Reproduction

Pregnancy—
Tc 99m (as free pertechnetate) crosses the placenta. Although studies have not been done with technetium Tc 99m bicisate in humans, the estimated absorbed radiation dose to the uterus is 6.99 mGy/1110 MBq (0.69 rad/30 mCi) for a 2-hour void, and 12.2 mGy/1110 MBq (1.23 rad/30 mCi) for a 4.8-hour void. There is no evidence demonstrating embryonic or fetal harm at these doses. {05}

Nevertheless, the possibility of pregnancy should be assessed in women of child-bearing potential. In these situations, the physician should use discretion and reduce the administered activity of the radiopharmaceutical to the lowest possible amount. {02}

Studies have not been done in animals. {01}

FDA Pregnancy Category C. {01}

Breast-feeding

Although it is not known whether technetium Tc 99m bicisate 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. {04}

Pediatrics

There have been no specific studies evaluating the safety and efficacy of technetium Tc 99m bicisate in pediatric patients. However, no pediatrics-specific problems have been documented to date. {01}


Geriatrics


Diagnostic studies performed to date using technetium Tc 99m bicisate have not demonstrated geriatrics-specific problems that would limit the usefulness of technetium Tc 99m bicisate in the elderly. {01} {07} {14} {22} {24} {25}

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 rare
    
Angina {01}(chest pain)
    
difficulty breathing {01}
    
hallucinations {01}
    
hypertension {01}
    
seizures {01}
    
skin rash {01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence rare
    
Agitation or anxiety {01}{05}
    
dizziness {01}
    
drowsiness {01}
    
headache {01}
    
nausea{01}{05}
    
parosomia (transient, mild, pleasant aromatic odor){01}{05}





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 bicisate in brain

Retention of radioactivity in brain 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; reducing administered activity should be considered





Breast-feeding—Not known if technetium Tc 99m bicisate 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

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

Precautions after having this test
Adequate intake of fluids before and after administration of technetium Tc 99m bicisate; voiding frequently for 2 to 6 hours after administration to promote urine flow and to minimize absorbed radiation dose to bladder


Side/adverse effects
Signs of rare, but possible, side effects, especially angina, difficulty breathing, hallucinations, hypertension, seizures, and skin rash


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 administration of technetium Tc 99m bicisate to promote urinary flow and blood pool clearance. Also, urination is recommended as often as possible for 2 to 6 hours after the examination to promote urine flow, thereby minimizing absorbed radiation dose to the bladder. {01}

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. {03}


Parenteral Dosage Forms

TECHNETIUM Tc 99m BICISATE INJECTION

Usual adult and adolescent administered activity
Brain imaging
Intravenous, 370 to 1110 megabecquerels (10 to 30 millicuries). {01} {05}


Usual pediatric administered activity
Safety and dosage have not been established. {01}

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

Strength(s) usually available
U.S.—


0.9 mg bicisate dihydrochloride, 0.36 mg edetate disodium (dihydrate), 72 mcg (0.072 mg) stannous chloride dihydrate (theoretical), 12 mcg (0.012 mg) stannous chloride dihydrate (minimum), 83 mcg (0.083 mg) total tin (dihydrate) and 24 mg mannitol, in lyophilized form under nitrogen atmosphere, per reaction vial A; and 4.1 mg sodium phosphate dibasic heptahydrate, 0.46 mg sodium phosphate monobasic monohydrate, and enough water for injection to produce 1 mL, per reaction vial B (Rx) [Neurolite{01}]

Canada—


0.9 mg bicisate dihydrochloride, 0.36 mg edetate disodium (dihydrate), 72 mcg (0.072 mg) stannous chloride dihydrate (theoretical), 12 mcg (0.012 mg) stannous chloride dihydrate (minimum), 83 mcg (0.083 mg) total tin (dihydrate) and 24 mg mannitol, in lyophilized form under nitrogen atmosphere, per reaction vial A; and 4.1 mg sodium phosphate dibasic heptahydrate, 0.46 mg sodium phosphate monobasic monohydrate, and enough water for injection to produce 1 mL, per reaction vial B (Rx) [Neurolite{05}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. {01} {05}

Note: Prior to labeling, kit can be stored between 15 and 25 °C (59 and 77 °F). {01} {05}


Preparation of dosage form:
To prepare injection, an oxidant-free sodium pertechnetate Tc 99m solution is used. See manufacturer's package insert for instructions. {01}

Stability:
Technetium Tc 99m bicisate is stable at room temperature for a period of at least 8 hours after reconstitution. {06} However, the manufacturer's package insert recommends that the product be used within 6 hours after preparation. {01} {28}

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. {01}

Note: Caution—Radioactive material.




Developed: 06/29/1995



References
  1. Neurolite package insert (Du Pont Merck—US), New 11/94, Rec 2/95.
  1. Standard statement agreed upon by USP Radiopharmaceuticals Panel during 05/08/91 meeting.
  1. Reviewers' responses to Ballot of 5/11/94.
  1. Standard statement agreed upon by USP Radiopharmaceuticals Panel for technetium Tc 99m-labeled radiopharmaceuticals.
  1. Neurolite package insert (Du pont—Canada), New 2/95, Rec 2/95.
  1. Personal communication, Radiopharmaceutical Research, Du Pont, 2/16/95.
  1. Villanueva-Meyer J, Garrett K, Kuperus J, et al. Size of perfusion defect in completed stroke studied with Tc-99m ECD, correlation with CT. Eur J Nucl Med 1988; 149(5/6): 310
  1. Matsuda H, Li YM, Higashi S, et al. Comparative SPECT study of stroke using Tc-99m ECD, I-123 IMP, and Tc-99m HMPAO. Clin Nucl Med 1993 Sep; 18(9): 754-8.
  1. Holman BL, Hellman RS, Goldsmith SJ, et al. Biodistribution, dosimetry, and clinical evaluation of technetium-99m ethyl cysteinate dimer in normal subjects and in patients with chronic cerebral infarction. J Nucl Med 1989 Jun; 30(6): 1018-24.
  1. Léveillé J, Demonceau G, De Roo M, et al. Characterization of technetium-99m-L, L-ECD for brain perfusion imaging, part 2: biodistribution and brain imaging in humans. J Nucl Med 1989; 30(11): 1902-10.
  1. Vallabhajousla S, Zimmerman RE, Picard M, et al. Technetium-99m ECD: a new brain imaging agent: in vivo kinetics and biodistribution studies in normal human subjects. J Nucl Med 1989 May; 30(5): 599-604.
  1. Devous MD Sr, Leroy RF, Payne JK, et al. Comparison of Tc-99m ECD to Xe-133 in the SPECT determination of regional cerebral blood flow in patients with mild perfusion abnormalities. J Nucl Med 1990 May; 31(5): 817.
  1. Lassen NA. Pathophysiology of brain ischemia as it relates to the therapy of acute ischemic stroke. Clin Neuropharmacol 1990; 13(Suppl 3): S1-S8.
  1. Videbaek C, Andersen A, Waldemar G, et al. Tc-ECD distribution in the brain corresponds closely to regional cerebral blood flow. J Neurol 1990; 237(Suppl 1): S15.
  1. Castagnoli A, Borsato N, Bruno A, et al. SPECT brain imaging in chronic stroke and dementia: a comparison of Tc 99m-ECD and Tc 99m-HMPAO. In: Hartmann A, Hoyer S, Kuschinksi W, editors. Cerebral ischemia and dementia. Stuttgart: Springer-Verlag, 1991: 327-33.
  1. Greenberg JH, Araki N, Karp A, et al. Quantitative measurement of regional cerebral blood flow in focal cerebral ischemia using Tc-99m ECD. J Nucl Med 1991; 32(5): 1070.
  1. Ogawa Y, Nishimura T, Hayashida K, et al. Cerebral perfusion scintigraphy in patients with cerebrovascular disease by using Tc-99m ECD: comparative study with I-123 IMP SPECT. Kaku Igaku 1991 Jun; 28(6): 599-607.
  1. Walovitch RC, Franceschi M, Picard M, et al. Metabolism of Tc-99m-L, L-ethyl cysteinate dimer in healthy volunteers. Neuropharmacol 1991 Mar; 30(3): 283-92.
  1. Léveillé J, Demonceau G, Walovitch RC. Intrasubject comparison between technetium-99m-ECD and technetium-99m-HMPAO in healthy human subjects. J Nucl Med 1992 Apr; 33: 480-4.
  1. Walovitch RC, Joseph JL, LaFrance ND. Neurolite imaging of cross cerebellar diaschisis in stroke. J Nucl Med 1992 May; 33(5): 968.
  1. Menzel C, Grünwald F, Broich K, et al. Tc-99m-ECD brain SPECT in stroke: evaluation of time dependent tracer distribution. J Nucl Med 1993; 34(5S): 204P.
  1. Brass LM, Walovitch RC, Joseph JL, et al. The role of single photon emission computed tomography brain imaging with Tc-99m-bicisate in the localization and definition of mechanism of ischemic stroke. J Cereb Blood Flow Metab 1994; 14(Suppl 1): S91-S98.
  1. Greenberg JH, Araki N, Karp A. Correlation between Tc-99m-bicisate and regional CBF measured with iodo-[ 14C]antipyrine in a primate focal ischemia model. J Cereb Blood Flow Metab 1994; 14(Suppl 1): S36-S43.
  1. Nakagawara J, Nakamura J, Takeda R, et al. Assessment of postischemic reperfusion and Diamox activation test in stroke using Tc-99m-ECD SPECT. J Cereb Blood Flow Metab 1994; 14(Suppl 1): S49-S57.
  1. Shishido F, Uemura K, Murakami M, et al. Cerebral uptake of Tc-99m-bicisate in patients with cerebrovascular disease in comparison with CBF and CMRO;I2 measured by positron emission tomography. J Cereb Blood Flow Metab 1994; 14(Suppl 1): S66-S75.
  1. Tamgac F, Moretty JL, Defer G, et al. Non-matched images with I-123-IMP and Tc-99m-bicisate single photon emission tomography in the demonstration of focal hyperaemia during the subacute phase of an ischaemic stroke. Eur J Nucl Med 1994 Mar; 21(3): 254-7.
  1. Grünwald F, Sakowski R, Elger CE, et al. Ictal and interictal brain SPECT imaging in epilepsy using technetium-99-ECD. J Nucl Med 1994 Dec; 35(12): 1896-901.
  1. Reviewers' comments per monograph revision of 3/6/95.
  1. Holman BL, Devous MD Sr. Functional brain SPECT: the emergence of a powerful clinical method. J Nucl Med 1992; 33: 1888-904.
  1. Masdeu JC, Brass LM, Holman BL, et al. Brain single-photon emission computed tomography. Neurology 1994; 44: 1970-7.
  1. Moretti JLM, Tamgac F, Weinmann P, et al. Early and delayed brain SPECT with technetium-99m-ECD and iodine-123-IMP in subacute strokes. J Nucl Med 1994; 35: 1444-9.
  1. Walovitch RC, Waldemar G, Andersen AR, et al. Relationship between Neurolite SPECT brain imaging and cognitive impairment in patients with Alzheimer's dementia. J Neuroimaging 1993; 3(1): 73.
  1. Waldemar G, Walovitch RC, Andersen AR, et al. Tc-99m bicisate (Neurolite) SPECT brain imaging and cognitive impairment in dementia of the Alzheimer type: a blinded read of image sets from a multicenter SPECT trial. J Cereb Blood Flow Metab 1994; 14(Suppl 1): S99-S105.
  1. Packard AB, Roach PJ, Davis RT, et al. Ictal SPECT with Tc-99m-bicisate in children with refractory epilepsy. J Nucl Med 1994; 35(5S): 134P.
  1. Grünwald F, Menzel C, Pavics L, et al. Ictal and interictal brain SPECT imaging in epilepsy using technetium-99m-ECD. J Nucl Med 1994; 35: 1896-901.
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