1 Name of Medicine
2 Qualitative and Quantitative Composition
This kit formulation consists of two nonradioactive vials: vial A contains bicisate dihydrochloride (N, N'-1,2-ethylenediylbis-L-cysteine diethyl ester dihydrochloride) and a reducing agent as a lyophilized solid and vial B contains a buffer solution. Both vials are sterile, non-pyrogenic, and contain no preservative.
Vial A. Bicisate dihydrochloride 0.9 mg, mannitol 24 mg, disodium edetate 0.36 mg, stannous chloride, and dihydrate 72 microgram.
The contents of vial A are lyophilized and stored under nitrogen. The pH of the solution before lyophilization is 2.7 ± 0.25.
Vial B. Dibasic sodium phosphate heptahydrate 4.1 mg, monobasic sodium phosphate monohydrate 0.46 mg, and water for injection qs 1 mL.
The contents of vial B are stored under air. The pH of the solution is 7.6 ± 0.4.
3 Pharmaceutical Form
White powder, crystalline material or plug for the preparation of (99mTc) bicisate intravenous injection.
4.1 Therapeutic Indications
[99mTc] bicisate scintigraphy is indicated in the evaluation and localization of regional perfusion abnormalities in adult patients with the central nervous system disorders of stroke and dementia.
4.2 Dose and Method of Administration
This drug is administered by intravenous injection for diagnostic use after reconstitution with sterile, non-pyrogenic, sodium pertechnetate [99mTc] injection BP.
The recommended dose for intravenous administration after preparation with sodium pertechnetate [99mTc] Injection BP, in the average patient (70 kg) is 740 MBq. Scintigraphy should be carried out within 6 hours of administration.
The patient dose should be measured by a suitable radioactivity calibration prior to patient administration. It is recommended to check the radiochemical purity prior to patient administration.
If the patient's status allows, the patient should be encouraged to drink plenty of fluids and void frequently at two hour intervals for at least six hours. This will decrease the radiation exposure to the dose limiting organ, the bladder wall.
Instructions for preparation of technetium [99mTc] bicisate. Preparation of the technetium [99mTc] bicisate from the Neurolite kit is done by the following aseptic procedure:
a. Prior to adding the sodium pertechnetate [99mTc] Injection to vial B (the buffer vial), write the estimated activity, date, and time of preparation in the space provided on the vial label. Then tear off a radiation symbol and attach it to the neck of the vial.
b. Waterproof gloves should be worn during the preparation procedure. Remove the plastic disc from both vials and swab the top of each vial closure with alcohol to disinfect the surface.
c. Place vial B in a suitable radiation shield appropriately labeled with date, time of preparation, volume and activity.
d. With a sterile shielded syringe, aseptically add 3.70 GBq sterile, nonpyrogenic, sodium pertechnetate [99mTc] injection, in approximately 2.0 mL, to vial B.
e. With a sterile shielded syringe, rapidly inject 3.0 mL of sodium chloride injection (0.9%) into vial A (the lyophilized vial) to dissolve the contents. Shake the contents of the vial for a few seconds.
f. With another sterile syringe, immediately (within 30 seconds) transfer 1.0 mL of vial A solution to vial B. Discard the remaining Vial A contents.
g. Swirl the contents of the vial for a few seconds, and allow this mixture to stand for thirty (30) minutes at room temperature.
h. Examine the vial contents for particulates and discoloration prior to injection using appropriate radiation protection.
i. Assay the reaction vial using a suitable radioactivity calibration system. Record the technetium [99mTc] concentration, total volume, assay time and date, expiration time and lot number on the vial shield label and affix the label to the shield.
j. Store the reaction vial containing the [99mTc] bicisate at room temperature (15-30°C) until use; at such time the product should be aseptically withdrawn. The vial contains no preservative.
Waste must be disposed of according to national regulations for radioactive material.
Note. It is important to strictly adhere to the above product reconstitution. Product should be used within 6 hours after preparation.
Determination of radiochemical purity. The quality control of the agent should follow the procedure shown below.
Materials for TLC procedure. Baker-Flex silica gel IB-F, 2.5 x 7.5 cm, Baker #2/4463/03.
Solvent system: ethyl acetate, HPLC grade.
Dose calibrator or gamma counter for measuring radioactivity.
Small chromatographic developing tank.
Syringe and shielded vials, as needed.
TLC procedure. Establish the radiochemical purity of the final solution by thin layer chromatography (TLC) using Baker-Flex silica gel IB-F plates and a solvent system of ethyl acetate.
Procedure: using fresh ethyl acetate pour enough solvent into the developing tank to a depth of 3 to 4 mm. Seal the tank with parafilm and allow 15 to 40 minutes for solvent equilibration. It is important to pre-equilibrate and preserve the integrity of the headspace in the chromatography tank, otherwise unreproducible TLC results are obtained.
Note. Ethyl acetate is a skin/ mucous membrane irritant and should be handled in a hood whenever possible.
With a pencil, draw a faint line across the TLC plate at heights of two (2) cm, four and one half (4.5) cm and seven (7) cm from the bottom of the TLC plate.
Place approximately 5 microliters of the final solution at the center of the 2 cm mark. This can be accomplished using a syringe fitted with a 25 or 27 gauge needle and allowing a drop to form while holding the syringe in a vertical position. The diameter of the spot should not be greater than 10 mm. Allow the spot to dry for 5 to 10 minutes, no longer.
Place the plate in the pre-equilibrated TLC tank and develop to the 7.0 cm line (about 15 minutes). Remove the plate and dry in a ventilated area.
Quantification. Cut the TLC plate at the 4.5 cm mark with scissors. Count the activity on each piece using a dose calibrator or a gamma counter. The top portion contains the Tc-99m bicisate and the bottom portion contains all radioimpurities. Calculate the radiochemical purity using Equation 1:
Criteria. [99mTc] bicistate has an Rf of 0.9 (± 0.1); colloid, TcO4- and Tc-99m EDTA remain at the origin. If the radiochemical purity is less than 90%, do not use the kit and discard the preparation.
Radiation dosimetry. The projected radiation doses to organs and tissues of an average (70 kg) patients after intravenous injection of [99mTc] bicisate are shown in Table 1.*
*Dosimetry calculated using the MIRD method at Oak Ridge Associated Universities, P.O. Box 117, Oak Ridge, TN 20 July 1992; Effective Dose calculated according to the method of ICRP 60.
There are no known contraindications.
4.4 Special Warnings and Precautions for Use
General. This medical product is for diagnostic use only.
Radiopharmaceuticals should be used only by 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 government agency authorized to license the use of radionuclides.
The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spills of urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must therefore be taken.
For each patient, exposure to ionizing radiation must be justifiable on the basis of likely benefit. The activity administered must be such that the resulting radiation dose is as low as reasonably achievable bearing in mind the need to obtain the intended diagnostic or therapeutic result.
Exposure to ionizing radiation is linked with cancer induction and a potential for the development of hereditary defects. For diagnostic nuclear medicine investigations, the current evidence suggests that these adverse effects will occur with low frequency because of the low radiation doses incurred. For most diagnostic investigations using nuclear medicine procedure, the radiation dose delivered is less than 20 mSv (EDE). Higher doses may be justified in some clinical circumstances.
Use in renal impairment. 99mTc-bicisate is excreted via the kidney. The radiation dose may increase substantially in patients with impaired kidney function or obstruction to urinary flow.
Safety and effectiveness have not been established in adult patients with renal function impairment. High cerebral blood flow might be underestimated.
Patients should be encouraged to drink fluids and to void frequently during the 2-6 hours immediately after injection to minimize radiation dose to the bladder and other target organs.
Contents of vial A and vial B are intended only for use in the preparation of technetium [99mTc] bicisate injection and are not to be administered directly to the patient.
The contents of each vial are sterile and nonpyrogenic. To maintain sterility, aseptic technique must be used during all operations in the manipulation and administration of Neurolite.
Technetium [99mTc] bicisate should be used within six hours of the time of preparation.
As with any other radioactive material, appropriate shielding should be used to avoid unnecessary radiation exposure to the patient, occupational workers, and other people.
Use in the elderly. No data available.
Paediatric use. Safety and effectiveness in children below the age of 18 have not been established.
Effects on laboratory tests. No data available.
4.5 Interactions with Other Medicines and Other Forms of Interactions
No data available.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility. Studies have not been conducted to evaluate effects on fertility.
Animal reproduction studies have not been conducted with technetium [99mTc] bicisate. It is also not known whether technetium [99mTc] bicisate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Therefore, technetium [99mTc] bicisate should not be administered to a pregnant woman unless the potential benefit justifies the potential risk to the fetus.
Formula feedings should be substituted for breast feedings for at least 24 hours.
4.7 Effects on Ability to Drive and Use Machines
The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
4.8 Adverse Effects (Undesirable Effects)
In clinical trials, Neurolite has been administered to 1063 subjects (255 normals, 808 patients). Of these, 566 (53%) were men, 494 (47%) were women and 3 (0.3%) of the patient's genders were not recorded. The mean age was 58 years (range 17 to 92 years). In the 808 patients, who had experienced neurologic events, there were 11 (1.4%) deaths, none of which were attributed to Neurolite. A total of 61 subjects experienced adverse reactions; the adverse reaction rates were comparable in the < 65 year, and the > 65 year age groups. Adverse events reported at a rate of 0.5% or greater after Neurolite administration are shown in Table 2.
The following adverse effects were observed in ≤ 0.5% of the subjects: dizziness, malaise/ somnolence, parosmia, hallucinations, rash, syncope, cardiac failure, hypertension, angina, and apnea/ cyanosis.
In clinical trials of 197 patients, there were inconsistent changes in the serum calcium and phosphate levels. The cause of the changes has not been identified and their frequency and magnitude have not been clearly characterized. None of the changes required medical intervention.
Postmarketing. The following adverse effects were observed in < 0.5% of the patient population. See Table 3.
Reporting suspected adverse effects. Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.
With a diagnostic radiopharmaceutical classical overdosage does not occur. However, in order to decrease radiation exposure the patient should be encouraged to drink plenty of fluids and void frequently. In the event of accidental overdose in order to decrease radiation exposure the patient should be encouraged to drink plenty of fluids and void frequently.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action. Due to the low concentrations administered pharmacodynamic actions of [99mTc] bicisate are not expected.
Clinical trials. Two clinical trials were performed in a total of 359 subjects (273 with stroke, 86 normal). Of these 56% were men and 44% were women. The mean age was 60.2 years (range 23 to 92 years). Subjects were 87.2% Caucasian, 8.4% Black, 2.2% Hispanic, 1.7% Oriental and 0.6% other.
Eligible patients had a confirmed stroke. Patients with other brain lesions were not evaluated. Subjects received Neurolite (mean dose range 370-1,110 MBq) and underwent SPECT imaging and either CT or MRI scans within 0-30 days of the onset of signs and symptoms of stroke. CT or MRI and the administration of Neurolite occurred at different and variable times after the onset of a stroke. The effect of the timing on the accuracy of the images cannot be evaluated. The Neurolite scan results were blindly compared to unblinded CT/MRI results, the short standardized neurologic examination (SSNE) and the final diagnosis (e.g. the overall combined clinical impression with CT/MRI and SSNE).
In these studies, at least one of three blinded readers made a diagnosis of stroke in 190 (85%) of the Neurolite SPECT studies and in 238 (88%) CT/MRI studies. The sensitivity and specificity for overall image evaluation in these two trials was 74.4%, 61.2% and 87.8%, 97.6% respectively1. The Neurolite and CT/MRI imaging results versus the SSNE and final diagnosis were comparable. Neurolite had 11 false positive and 34 false negatives. CT/MRI had 0 false positive and 31 false negatives. Both Neurolite and CT/MRI missed strokes (true positives) that were identified by the other modality. The majority of the false negatives in either modality were within 15 days of the clinical stroke.
The trials were not designed to determine when Neurolite or CT/MRI studies could become positive in relationship to the time of the stroke. The relevance of the Neurolite scan results to the prediction of neurologic function or brain cell viability is not known. Also, not known is the ability of the Neurolite findings to distinguish between a stroke and pre-existing CNS lesions. Neurolite should not be used for these purposes (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
1The sensitivity and specificity for the comparators, MRI/CT, was not determined. Comparator testing was not done in a blinded read fashion. These evaluations were done with the readers knowing the complete patient history in most cases.
One clinical trial, designed to evaluate efficacy of 99mTc-bicisate as a regional cerebral perfusion flow marker and compare 99mTc-bicisate and 99mTc-exametazime images, was performed in a total of 124 patients. 118 of these patients (51 stroke, 71 dementia, 1 TIA) had imaging studies with both imaging agents and were included in the efficacy analysis. Of the evaluable patients, twenty-two (65%) of the stroke patients and 25 (50%) of the dementia patients were men; 12 (35%) of the stroke patients and 25 (50%) of the dementia patients were women. The mean age was 64.7 years (range 32 to 89 years).
Eligible patients had a confirmed chronic stroke or dementia. 99mTc-bicisate and 99mTc-exametazime images were acquired after administration of an equivalent of each agent (mean dose range 555-1,110 MBq) in random order two to eight days apart. An intrasubject comparison of SPECT brain images of 99mTc-bicisate and 99mTc-exametazime was performed using a relative quantitative rating scale which was reflective of the level of tracer activity. The degree of agreement between the two tracers in localizing normal and abnormal brain regions was determined. In addition, a transverse slice with at least one perfusion abnormality on both images was selected and region of interest analysis was performed to determine lesion to normal tissue ratios.
The results of this study shows that the intracerebral distribution of these two tracers is very similar in stable stroke patients and demented subjects. 99mTc-bicisate localized 80% of all 99mTc-exametazime abnormalities, while as a result of the greater prevalence of 99mTc-bicisate abnormalities, 99mTc-exametazime only localized 9-20% of 99mTc-bicisate abnormalities. When all brain regions were analyzed (regions with abnormal and normal tracer activity), the 99mTc-bicisate and 99mTc-exametazime images were in agreement for 84% of the brain regions. Region of interest analyses generally showed a slightly greater contrast between the normal and lesioned brain regions for 99mTc-bicisate as compared with 99mTc-exametazime.
5.2 Pharmacokinetic Properties
After reconstitution of the Neurolite kit with Sodium Pertechnetate [99mTc] Injection BP, the complex [99mTc] N, N'-1,2-ethylenediyl) bis-L-cysteine diethyl ester, [99mTc] bicisate, is formed.
[99mTc] bicisate can exist in four stereochemically distinct forms depending upon the stereochemistry of the bicisate moiety. Studies have demonstrated a stereoselective brain retention and metabolism of only the L,L derivate. In contrast, the Tc-99m complex derived from the D,D isomer crosses the blood-brain barrier and is extracted by the brain, however, it is neither retained nor metabolized to any appreciable extent. Thus, only the L,L isomer is used in Neurolite.
Studies in healthy volunteers indicate a good initial brain uptake of [99mTc] bicisate with values ranging between 4.8-6.5% of the injected dose within a few minutes of injection. Brain uptake and retention of [99mTc] bicisate is sufficient to allow SPECT brain imaging to occur immediately after dose administration. The brain washout of [99mTc] bicisate is very slow. Its brain distribution pattern is unchanged for at least six hours postinjection and is similar to that seen with the cerebral blood flow standard Xenon Xe-133 gas.
Elimination of [99mTc] bicisate from the blood is rapid, resulting in less than 5% of the injected dose remaining in the blood by one hour postadministration. Within five minutes of [99mTc] bicisate administration, most of the activity in the venous blood is in the form of metabolites. On average, 74% of the injected dose is excreted in the urine within the first 24 hours postinjection, with up to 50% of the injected dose excreted within the first two hours. Because the urinary bladder wall is the critical dose organ and because of the rapid urinary clearance of [99mTc] bicisate, dosimetry can be favorably reduced by increasing the frequency of bladder voiding. [99mTc] bicisate and its major metabolite are not bound to serum proteins.
In humans, similar to other [99mTc] labeled brain imaging agents, it has been shown that an elevation in blood flow over that of normal physiological levels will result in an underestimation of relative flow.
A pharmacokinetic study of [99mTc] bicisate has not been performed in patients with neurological conditions. However, the intracerebral distribution of a single dose of [99mTc] bicisate has been evaluated in patients, over time, by repeat SPECT imaging performed by two investigators, and the resulting [99mTc] bicisate images showed the same overall intracerebral distribution as the initial imaging study. Thus suggesting that, like in neurologically normal subjects, the distribution of [99mTc] bicisate, is unchanged over time.
5.3 Preclinical Safety Data
Genotoxicity. When tested in vitro, Neurolite prepared with decayed generator eluate induced unscheduled DNA synthesis in rat hepatocytes and caused an increased frequency of sister chromatid exchanges in CHO cells; but, it did not induce chromosome aberrations in human lymphocytes or cause gene mutations in the Ames test or in a CHO/HGPRT test. Unreacted bicisate dihydrochloride increased the apparent rate of gene mutation of the TA 97a strain of S. typhimurium in the Ames test; but, it did not demonstrate clastogenic activity in an in vivo micronucleus assay in mice. The maximum tolerated dose of bicisate dihydrochloride is 25 mg/kg IV.
Carcinogenicity. Studies have not been conducted to evaluate carcinogenic potential.
6 Pharmaceutical Particulars
6.1 List of Excipients
See Section 2 Qualitative and Quantitative Composition.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
The contents of vial A are lyophilized and stored under nitrogen. This vial is stored at below 25°C. Protect from light.
The contents of vial B are stored under air. This vial is stored at below 25°C.
The product should be stored below 25°C and protected from light. The contents of the kit before preparation are not radioactive. However, after Sodium Pertechnetate [99mTc] Injection is added, adequate shielding of the final preparation must be maintained. The reconstituted product should be stored at room temperature (15-30°C).
Storage of radiopharmaceuticals should be in accordance with national regulations on radioactive materials (Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) website (www.arpansa.gov.au).
6.5 Nature and Contents of Container
Neurolite is supplied in packs of two (2) vials of A and two (2) vials of B and in packs of five (5) vials of A and five (5) vials of B, sterile and nonpyrogenic. Technetium [99mTc] bicisate contains no preservatives.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements and the Code for Disposal of Solid Radioactive Waste (RPS C-6).
7 Medicine Schedule (Poisons Standard)
Summary Table of Changes