TECHNETIUM TC 99M SESTAMIBI (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In comparison with most other diagnostic technetium labeled radiopharmaceuticals, the radiation dose to the ovaries (1.5 rads/30 mCi at rest, 1.2 rads/30 mCi at exercise) is high. Minimal exposure (ALARA) is necessary in women of childbearing capability [see Dosage and Administration (2.2)].

The active intermediate, Cu(MIBI)4 BF4 , was evaluated for genotoxic potential in a battery of five tests. No genotoxic activity was observed in the Ames, CHO/HPRT and sister chromatid exchange tests (all in vitro). At cytotoxic concentrations(> 20 mcg/mL), an increase in cells with chromosome aberrations was observed in the in vitro human lymphocyte assay. Cu(MIBI)4 BF4 did not show genotoxic effects in the in vivo mouse micronucleus test at a dose which caused systemic and bone marrow toxicity (9 mg/kg, > 600 x maximal human dose).

14 CLINICAL STUDIES

Clinical Trials:

Myocardial Imaging: In a trial of rest and stress Tc 99m Sestamibi imaging, the relationship of normal or abnormal perfusion scans and long term cardiac events was evaluated in 521 patients (511 men, 10 women) with stable chest pain. There were 73.9 % Caucasians, 25.9 % Blacks and 0.2 % Asians. The mean age was 59.6 years (range: 29 to 84 years). All patients had a baseline rest and exercise Tc 99m Sestamibi scan and were followed for 13.2 ± 4.9 months (range: 1 to 24 months). Images were correlated with the occurrence of a cardiac event (cardiac death or non-fatal myocardial infarction). In this trial as summarized in Table 7, 24/521 (4.6 %) had a cardiac event.

Table 7. Cardiac Events
Baseline Scan(a)

Proportion of patients

with events by scan results(a)
Proportion of scan result in patients with events; N=24(a) Proportion of event-free patients by scan result(a)
Normal 1/206 (0.5 %) 1/24 (4.2 %) 205/206 (99.5 %)
Abnormal 23/315 (7.3 %)(b) 23/24 (95.8 %)(b) 292/315 (92.7 %)(b)

(a) Note: Similar findings were found in two studies with patients who had pharmacologic stress Tc 99m Sestamibi imaging.(b) p<0.01

Although patients with normal images had a lower cardiac event rate than those with abnormal images, in all patients with abnormal images it was not possible to predict which patient would be likely to have further cardiac events; i.e., such individuals were not distinguishable from other patients with abnormal images.

The findings were not evaluated for defect location, disease duration, specific vessel involvement or intervening management.

In earlier trials, using a template consisting of the anterior wall, inferior-posterior wall and isolated apex, localization in the anterior or inferior-posterior wall in patients with suspected angina or coronary artery disease was shown. Disease localization isolated to the apex has not been established. In adults, Tc 99m Sestamibi has not been studied or evaluated in cardiac disorders other than coronary artery disease.

Breast Imaging: Technetium Tc 99m Sestamibi was evaluated in two multicenter, clinical trials of a total of 673 woman patients. Overall the mean age was 52 (range 23 to 87 years). The racial and ethnic representation was 70% Caucasian, 15 % African-American, 14 % Hispanic and 1% Asian.

Both clinical studies evaluated women who were referred for further evaluation for either: 1) a mammographically detected (with varying degrees of malignant likelihood) but not palpable breast lesion (study A, n=387, mean age = 54 years), or 2) a palpable breast lesion (study B, n=286, mean age = 50 years). In both studies all patients were scheduled for biopsy.

Technetium Tc 99m Sestamibi (20 to 30 mCi) was injected intravenously in a vein that was contralateral to the breast lesion in question. Planar imaging was completed with a high resolution collimator with a 10 % window centered at 140 keV, and 128 x 128 matrix. An initial marker image, that was not used in the data analysis, was obtained using a cobalt Co57 point source as a marker of a palpable mass. Images were obtained 5 minutes after injection as follows: lateral image of the affected breast for 10 minutes, lateral image of the contralateral breast for 10 minutes, and an anterior image of both breasts for 10 minutes. For the lateral image the patients were positioned in a prone position. For the anterior image, the patients were supine. The Technetium Tc 99m Sestamibi scintigraphic images were read in a randomized method by two groups of three blinded readers. Technetium Tc 99m Sestamibi uptake was scored as: normal (no uptake), equivocal, low, moderate, or high uptake. The results of Technetium Tc 99m Sestamibi images and mammography were analyzed in comparison to histopathologic findings of malignant or non-malignant disease.

As shown in Table 8 for the 483 evaluable patients, the sensitivity and specificity of any degree of Technetium Tc 99m Sestamibi uptake appear to vary with the presence or absence of palpable mass.

Table 8. Overall technetium Tc 99m Sestamibi Blinded Results of Target Lesions(a) Identified at Study Entry(b)
STATISTIC

Study A

Non-Palpable Mass and an

Study B

Number of Patients and Lesions N=277 Patients with 300 Lesions N=206 Patients with 240 Lesions
Sensitivity 52 (42,62)(c) 76 (67,83)
Specificity 94 (89,96) 85 (77,91)
PPV(d) 79 (67,88) 83 (74,89)
NPV(d) 80 (74,85) 78 (69,84)
Agreement 80 (75,85) 80 (75,85)
Prevalence 32 (27,37) 49 (43,56)

(a) Excludes all discordant lesions not identified at entry and excludes 25 equivocal interpretations from Study A and 32 equivocal interpretations from Study B (see Tables 9 and 10)

(b) some patients had more than one target lesion

(c) Median and approximated 95% Confidence Interval

In separate retrospective subset analyses of 259 patients with dense (heterogeneously/extremely dense) and 275 patients with fatty (almost entirely fat/numerous vague densities) breast tissue, the Technetium Tc 99m Sestamibi results were similar. Overall, the studies were not designed to compare the performance of Technetium Tc 99m Sestamibi with the performance of mammography in patients with breast densities or other coexistent breast tissue disorders

In general the histology seems to correlate with the degree of Technetium Tc 99m Sestamibi uptake. As shown in Tables 9 and 10 , the majority of the normal Technetium Tc 99m Sestamibi images are associated with non-malignant tissue (78 % to 81 %) and the majority of low, moderate or high uptake Technetium Tc 99m Sestamibi images are associated with malignant disease (79 % to 83 %). In an individual patient, however, the intensity of Technetium Tc 99m Sestamibi uptake can not be used to confirm the presence or absence of malignancy. Equivocal results do not have a correlation with histology.

Table 9. Degree of Technetium Tc 99m Sestamibi Breast Imaging Uptake in Comparison to Histopathology Results in Patients with Mammographically Detected Non-Palpable Lesions* (Study A)

Normal Uptake

Equivocal Uptake

Low, Moderate or

High Uptake

Non-malignant** 201 (81 %) 14 (56 %) 14 (21 %)
Malignant 48 (19 %) 11 (44 %) 52 (79 %)

* Median finding for 3 blinded readers

Table 10. Degree of Technetium Tc 99m Sestamibi Breast Imaging Uptake in Comparison to Histopathology Results in Patients with Palpable Lesions* (Study B)

Normal Uptake

Equivocal Uptake

Low, Moderate or

High Uptake

Non-malignant** 100 (78 %) 19 (59 %) 20 (17 %)
Malignant 29 (22 %) 13 (41 %) 95 (83 %)

* Median finding for 3 blinded readers

An estimate of the likelihood of malignancy based on the Technetium Tc 99m Sestamibi uptake score in combination with the mammographic score has not been studied.

In these two studies approximately 150 additional, non-biopsied lesions were found to be positive after Technetium Tc 99m Sestamibi imaging. These lesions were identified in sites that did not physically correlate with identified entry criteria mammographic lesions and these lesions were not palpable. These lesions were not biopsied. Whether these lesions were benign or malignant is not known. Technetium Tc 99m Sestamibi uptake can occur in both benign and malignant disease. THE CLINICAL USEFULNESS OF A POSITIVE Technetium Tc 99m Sestamibi IMAGE IN THE ABSENCE OF AN ABNORMAL MAMMOGRAM OR A PALPABLE LESION IS NOT KNOWN

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