CARDIOLITE Powder for solution, lyophilized Ref.[49661] Active ingredients: Technetium ⁹⁹ᵐTc sestamibi

Pulmonary activity is negligible even immediately after injection. Blood clearance studies indicate that the fast clearing component clears with a t_1/2 of 4.3 minutes at rest, and clears with a t_1/2 of 1.6 minutes under exercise conditions. At five minutes post injection about 8% of the injected dose remains in circulation. There is less than 1% protein binding of Technetium Tc99m Sestamibi in plasma. The myocardial biological half-life is approximately six hours after a rest or exercise injection. The biological half-life for the liver is approximately 30 minutes after a rest or exercise injection. The effective half-life of clearance (which includes both the biological half-life and radionuclide decay) for the heart is approximately 3 hours, and for the liver is approximately 30 minutes, after a rest or exercise injection. The ideal imaging time reflects the best compromise between heart count rate and surrounding organ uptake.

Myocardial uptake which is coronary flow dependent is 1.2% of the injected dose at rest and 1.5% of the injected dose at exercise. Table 6.0 illustrates the biological clearance as well as effective clearance (which includes biological clearance and radionuclide decay) of Tc99m Sestamibi from the heart and liver.

[Organ concentrations expressed as percentage of injected dose; data based on an average of 5 subjects at rest and 5 subjects during exercise].

Table 6.0 Biological and Effective Clearance:

A study in a dog myocardial ischemia model reported that Technetium Tc99m Sestamibi undergoes myocardial distribution (redistribution), although more slowly and less completely than thallous chloride Tl-201. A study in a dog myocardial infarction model reported that the drug showed no redistribution of any consequence. Definitive human studies to demonstrate possible redistribution have not been reported. In patients with documented myocardial infarction, imaging revealed the infarct up to four hours post dose.

12.3.1 Metabolism

The agent is excreted without any evidence of metabolism.

12.3.2 Elimination

The major pathway for clearance of Tc99m Sestamibi is the hepatobiliary system. Activity from the gall bladder appears in the intestines within one hour of injection. Twenty-seven percent of the injected dose is excreted in the urine, and approximately thirty-three percent of the injected dose is cleared through the feces in 48 hours.

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 Section 2).

The active intermediate, Cu(MIBI)₄BF₄, 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 µg/mL), an increase in cells with chromosome aberrations was observed in the in vitro human lymphocyte assay. Cu(MIBI)₄BF₄ 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 × maximal human dose).

MYOCARDIAL IMAGING

In a trial of rest and stress CARDIOLITE 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 CARDIOLITE 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 7.0, 24/521 (4.6%) had a cardiac event.

Table 7.0 Cardiac Events:

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, Tc99m Sestamibi has not been studied or evaluated in cardiac disorders other than coronary artery disease.

BREAST IMAGING

MIRALUMA 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.

MIRALUMA (20 – 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 × 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 MIRALUMA scintigraphic images were read in a randomized method by two groups of three blinded readers. MIRALUMA uptake was scored as: normal (no uptake), equivocal, low, moderate, or high uptake. The results of MIRALUMA images and mammography were analyzed in comparison to histopathologic findings of malignant or non-malignant disease.

As shown in Table 8.0 for the 483 evaluable patients, the sensitivity and specificity of any degree of MIRALUMA uptake appear to vary with the presence or absence of palpable mass.

TABLE 8.0 Overall MIRALUMA Blinded Results of Target Lesions^* Identified at Study Entry^†:

^* 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 9.0 and 10.0)
^† Some patients had more than one target lesion
^‡ Median and approximated 95% Confidence Interval
^§ PPV= Positive Predict Value; NPV= Negative Predict Value

In a 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 MIRALUMA results were similar. Overall, the studies were not designed to compare the performance of MIRALUMA 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 MIRALUMA uptake. As shown in Tables 9.0 and 10.0, the majority of the normal MIRALUMA images are associated with non-malignant tissue (78-81%) and the majority of low, moderate or high uptake MIRALUMA images are associated with malignant disease (79-83%). In an individual patient, however, the intensity of MIRALUMA uptake can not be used to confirm the presence or absence of malignancy. Equivocal results do not have a correlation with histology.

TABLE 9.0 Degree of MIRALUMA Breast Imaging Uptake in Comparison to Histopathology Results in Patients with Mammographically Detected Non-Palpable Lesions^* (Study A):

^* Median finding for 3 blinded readers
^† Includes benign tissue, fibroadenoma, benign intramammary nodes, radial scar.

TABLE 10.0 Degree of MIRALUMA Breast Imaging Uptake in Comparison to Histopathology Results in Patients with Palpable Lesions^* (Study B):

^* Median finding for 3 blinded readers
^† Includes benign tissue, fibroadenoma, benign intramammary nodes, radial scar.

An estimate of the likelihood of malignancy based on the MIRALUMA 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 MIRALUMA 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. MIRALUMA uptake can occur in both benign and malignant disease. THE CLINICAL USEFULNESS OF A POSITIVE MIRALUMA IMAGE IN THE ABSENCE OF AN ABNORMAL MAMMOGRAM OR A PALPABLE LESION IS NOT KNOWN.