2.1 Image Acquisition

Breast Imaging: It is recommended that images are obtained with a table overlay to separate breast tissue from the myocardium and liver, and to exclude potential activity that may be present in the opposite breast. For lateral images, position the patient prone with the isolateral arm comfortably above the head, shoulders flat against the table, head turned to the side and relaxed, with the breast imaged pendent through an overlay cutout. The breast should not be compressed on the overlay. For anterior images, position the patient supine with both arms behind the head. For either lateral or anterior images, shield the chest and abdominal organs, or remove them from the field of view.

For complete study, sets of images should be obtained five minutes after the injection, and in the following sequence:

Beginning five minutes after the injection of Technetium Tc 99m Sestamibi:

•

ten-minute lateral image of breast with abnormality

•

ten-minute lateral image of contralateral breast

•

ten-minute anterior image of both breasts

2.2 Radiation Dosimetry

The radiation doses to organs and tissues of an average patient (70 Kg) per 1110 MBq (30 mCi) of Technetium Tc 99m Sestamibi injected intravenously are shown in Table 1.

2.3 Instructions for Preparation

Preparation of the Technetium Tc 99m Sestamibi from the Kit for Preparation of Technetium Tc 99m Sestamibi for Injection is done by the following aseptic procedure:

Boiling Water Bath Procedure

1.

Prior to adding the Sodium Pertechnetate Tc 99m Injection to the vial, inspect the vial carefully for the presence of damage, particularly cracks, and do not use the vial if found. Tear off a radiation symbol and attach it to the neck of the vial.

2.

Waterproof gloves should be worn during the preparation procedure. Remove the plastic disc from the vial and swab the top of the vial closure with alcohol to sanitize the surface.

3.

Place the vial in a suitable radiation shield with a fitted radiation cap.

4.

With a sterile shielded syringe, aseptically obtain additive-free, sterile, non-pyrogenic Sodium Pertechnetate Tc 99m Injection [925-5550 MBq, (25–150 mCi)] in approximately 1 to 3 mL.

5.

Aseptically add the Sodium Pertechnetate Tc 99m Injection to the vial in the lead shield. Without withdrawing the needle, remove an equal volume of headspace to maintain atmospheric pressure within the vial.

6.

Shake vigorously, about 5 to 10 quick upward-downward motions.

7.

Remove the vial from the lead shield and place upright in an appropriately shielded and contained boiling water bath, such that the vial is suspended above the bottom of the bath, and boil for 10 minutes. Timing for 10 minutes is begun as soon as the water begins to boil again. Do not allow the boiling water to come in contact with the aluminum crimp.

8.

Remove the vial from the water bath, place in the lead shield and allow to cool for 15 minutes.

9.

Using proper shielding, the vial contents should be visually inspected. Use only if the solution is clear and free of particulate matter and discoloration.

10.

Assay the reaction vial using a suitable radioactivity calibration system. Record the Technetium Tc 99m concentration, total volume, assay time and date, expiration time and lot number on the vial shield label and affix the label to the shield.

11.

Store the reaction vial containing the Technetium Tc 99m Sestamibi at 20-25°C (68-77°F)[See USP] until use; at such time the product should be aseptically withdrawn. Technetium Tc 99m Sestamibi should be used within 6 hours of preparation. The vial contains no preservative.

 

Note: Adherence to the above product reconstitution instructions is recommended.

 

The potential for cracking and significant contamination exists whenever vials containing radioactive material are heated.

 

Product should be used within 6 hours after preparation.

 

Final product with radiochemical purity of at least 90% was used in the clinical trials that established safety and effectiveness. The radiochemical purity was determined by the following method.

 

Sun Pharmaceutical Industries, Inc.’s Kit for the Preparation of Technetium Tc 99m Sestamibi for Injection is not to be used with the Recon-o-Stat™ thermal cycler due to the smaller vial size requirements of this heating device.

2.4 Determination of Radiochemical Purity in Technetium Tc 99m Sestamibi

•

Obtain a Baker-Flex Aluminum Oxide coated, plastic TLC plate, #1 B-F, pre-cut to 2.5 cm x 7.5 cm.

•

Dry the plate or plates at 100°C for 1 hour and store in a desiccator. Remove pre-dried plate from the desiccator just prior to use.

•

Apply 1 drop of ethanol* using a 1 mL syringe with a 22–26 gauge needle, 1.5 cm from the bottom of the plate. THE SPOT SHOULD NOT BE ALLOWED TO DRY.

•

Add 2 drops of Technetium Tc 99m Sestamibi solution, side by side on top of the ethanol* spot. Return the plate to a desiccator and allow the sample spot to dry (typically 15 minutes).

•

The TLC tank is prepared by pouring ethanol* to a depth of 3–4 mm. Cover the tank and let it equilibrate for ~10 minutes.

•

Develop the plate in the covered TLC tank in ethanol* for a distance of 5 cm from the point of application.

•

Cut the TLC plate 4 cm from the bottom and measure the Tc 99m activity in each piece by appropriate radiation detector.

•

Calculate the % Tc 99m Sestamibi as:

*The ethanol used in this procedure should be 95% or greater. Absolute ethanol (99%) should remain at ≥ 95% ethanol content for one week after opening if stored tightly capped, in a cool dry place.

5.1 Warnings

In studying patients in whom cardiac disease is known or suspected, care should be taken to assure continuous monitoring and treatment in accordance with safe, accepted clinical procedure. Infrequently, death has occurred 4 to 24 hours after Tc 99m Sestamibi use and is usually associated with exercise stress testing (see Section 5.2).

Pharmacologic induction of cardiovascular stress may be associated with serious adverse events such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction and cerebrovascular events. Caution should be used when pharmacologic stress is selected as an alternative to exercise; it should be used when indicated and in accordance with the pharmacologic stress agent’s labeling.

Technetium Tc 99m Sestamibi has been rarely associated with acute severe allergic and anaphylactic events of angioedema and generalized urticaria. In some patients the allergic symptoms developed on the second injection during Tc 99m Sestamibi imaging. Patients who receive Technetium Tc 99m Sestamibi for either myocardial or breast imaging are receiving the same drug. Caution should be exercised and emergency equipment should be available when administering Technetium Tc 99m Sestamibi. Also, before administering Technetium Tc 99m Sestamibi Injection, patients should be asked about the possibility of allergic reactions to the drug.

5.2 General Precautions

The contents of the vial are intended only for use in the preparation of Technetium Tc 99m Sestamibi and are not to be administered directly to the patient without first undergoing the preparative procedure.

Radioactive drugs must be handled with care and appropriate safety measures should be used to minimize radiation exposure to clinical personnel. Also, care should be taken to minimize radiation exposure to the patients consistent with proper patient management.

Contents of the kit before preparation are not radioactive. However, after the Sodium Pertechnetate Tc 99m Injection is added, adequate shielding of the final preparation must be maintained. The components of the kit are sterile and non-pyrogenic. It is essential to follow directions carefully and to adhere to strict aseptic procedures during preparation.

Technetium Tc 99m labeling reactions depend on maintaining the stannous ion in the reduced state. Hence, Sodium Pertechnetate Tc 99m Injection containing oxidants should not be used.

Technetium Tc 99m Sestamibi should not be used more than six hours after preparation.

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.

Stress testing should be performed only under the supervision of a qualified physician and in a laboratory equipped with appropriate resuscitation and support apparatus.

The most frequent exercise stress test endpoints sufficient to stop the test reported during controlled studies (two-thirds were cardiac patients) were:

•

Fatigue 35%

•

Dyspnea 17%

•

Chest Pain 16%

•

ST-depression 7%

•

Arrhythmia 1%

8.1 Pregnancy

Risk Summary

Limited available data with Technetium Tc99m Sestamibi use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction and teratogenicity studies have not been conducted with Technetium Tc99m Sestamibi. However, all radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering Technetium Tc99m Sestamibi administration to a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from Technetium Tc99m Sestamibi and the gestational timing of exposure.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively

8.2 Lactation

Risk Summary

Limited data in the scientific literature on the presence of Technetium Tc99m Sestamibi in human milk, demonstrate that between 0.01% and 0.03% of maternal injected activity of technetium Tc99m Sestamibi was excreted in human milk. Technetium Tc99m Sestamibi accumulates in the lactating breast [see Clinical Considerations]. There are limited data in the scientific literature on effects of Technetium Tc99m Sestamibi on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Technetium Tc99m Sestamibi and any potential adverse effects on the breastfed infant from Technetium Tc99m Sestamibi or from the underlying maternal condition.

Clinical Considerations

Interruption of breastfeeding after exposure to Technetium Tc99m Sestamibi is not necessary because Technetium Tc99m Sestamibi excretion in breast milk is low. However, a lactating woman may restrict close contact with her breast fed infant to a maximum of 5 hours in the 24 hour period after Technetium Tc99m Sestamibi administration in order to minimize radiation exposure.

8.4 Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

No evidence of diagnostic efficacy or clinical utility of Technetium Tc99m Sestamibi scan was found in clinical studies of children and adolescents with Kawasaki disease.

A prospective study of 445 pediatric patients with Kawasaki disease was designed to determine the predictive value of Technetium Tc99m Sestamibi rest and stress myocardial perfusion imaging to define a pediatric population with Kawasaki disease that was at risk of developing cardiac events. Cardiac events were defined as cardiac death, MI, hospitalization due to cardiac etiology, heart failure, CABG or coronary angioplasty. The standard of truth was defined as cardiac events occurring 6 months following the administration of Technetium Tc99m Sestamibi. Only three cardiac events were observed at six months in this study. In all three cases, the scan was negative. No clinically meaningful measurements of sensitivity, specificity or other diagnostic performance parameters could be demonstrated in this study.

A ten year retrospective case history study of pediatric Kawasaki disease patients who completed Technetium Tc99m Sestamibi myocardial perfusion imaging and who had coronary angiography within three months of the Technetium Tc99m Sestamibi scan was designed to measure sensitivity and specificity of Technetium Tc99m Sestamibi scan. Out of 72 patients who had both evaluable Technetium Tc99m Sestamibi scans and evaluable angiographic images, only one patient had both an abnormal angiogram and an abnormal Technetium Tc99m Sestamibi scan. No clinically meaningful measurements of sensitivity, specificity or other diagnostic performance parameters could be demonstrated in this study.

In a clinical pharmacology study, 46 pediatric patients with Kawasaki disease received Technetium Tc99m Sestamibi administration at the following doses: 0.1-0.2 mCi/kg for rest, 0.3 mCi/kg for stress in one day studies; 0.2 mCi/kg for rest and 0.2 mCi/kg for stress in two day studies.

The radioactivity both in younger children and in adolescents exhibited PK profiles similar to those previously reported in adults (See Section 12).

The radiation absorbed doses in adolescents, both at rest and stress, were similar to those observed in adults (see Section 2). When comparing weight-adjusted radioactivity (up to 0.3 mCi/kg) doses administered to adolescents and younger children to the recommended dose administered to adults (up to 30 mCi ), the radiation absorbed doses in both adolescents and younger children were similar to those in adults.

Adverse events were evaluated in 609 pediatric patients from the three clinical studies described above. The frequency and the type of the adverse events were similar to the ones observed in the studies of Technetium Tc 99m Sestamibi in adults. Two of the 609 had a serious adverse event: one patient received a Technetium Tc 99m Sestamibi overdose but remained asymptomatic, and one patient had an asthma exacerbation following administration.

8.5 Geriatric Use

Of 3068 patients in clinical studies of the Kit for the Preparation of Technetium Tc 99m Sestamibi for myocardial imaging for injection, 693 patients were 65 or older and 121 were 75 or older.

Of 673 patients in clinical studies of the Kit for the Preparation of Technetium Tc 99m Sestamibi for breast imaging for injection, 138 patients were 65 or older and 30 were 75 or older.

Based on the evaluation of the frequency of adverse events and review of vital signs data, no overall differences in safety were observed between these subjects and younger subjects. Although reported clinical experience has not identified differences in response between elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

11.1 Physical Characteristics

Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours.1 Photons that are useful for detection and imaging studies are listed below in Table 3.

1Kocher, David, C., Radioactive Decay Data Tables, DOE/TIC-11026, 108(1981).

11.2 External Radiation

The specific gamma ray constant for Tc 99m is 5.4 microcoulombs/Kg-MBq-hr (0.78 R/mCi-hr) at 1 cm. The first half value layer is 0.017 cm of Pb. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 4.To facilitate control of the radiation exposure from Megabequerel (millicurie) amounts of this radionuclide, the use of a 0.25 cm thickness of Pb will attenuate the radiation emitted by a factor of 1,000.

 To correct for physical decay of this radionuclide, the fractions that remain at selected intervals after the time of calibration are shown in Table 5.

 * Calibration Time

12.1 Mechanism of Action

Technetium Tc 99m Sestamibi is a cationic Tc 99m complex which has been found to accumulate in viable myocardial tissue in a manner analogous to that of thallous chloride TI-201. Scintigraphic images obtained in humans after the intravenous administration of the drug have been comparable to those obtained with thallous chloride TI-201 in normal and abnormal myocardial tissue.

Animal studies have shown that myocardial uptake is not blocked when the sodium pump mechanism is inhibited. Although studies of subcellular fractionation and electron micrographic analysis of heart cell aggregates suggest that Tc 99m Sestamibi cellular retention occurs specifically within the mitochondria as a result of electrostatic interactions, the clinical relevance of these findings has not been determined.

The mechanism of Tc 99m Sestamibi localization in various types of breast tissue (e.g., benign, inflammatory, malignant, fibrous) has not been established.

12.3 Pharmacokinetics

Pulmonary activity is negligible even immediately after injection. Blood clearance studies indicate that the fast clearing component clears with a t½ of 4.3 minutes at rest, and clears with a t½ 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 Tc 99m 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 illustrates the biological clearance as well as effective clearance (which includes biological clearance and radionuclide decay) of Tc 99m 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.]

A study in a dog myocardial ischemia model reported that Technetium Tc 99m Sestamibi undergoes myocardial distribution (redistribution), although more slowly and less completely than thallous chloride TI-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 Tc 99m 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.

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 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 X maximal human dose).