Technetium

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.

1 INDICATIONS AND USAGE Myocardial Imaging: Kit for the preparation of Technetium Tc 99m Sestamibi Injection is a myocardial perfusion agent that is indicated for detecting coronary artery disease by localizing myocardial ischemia (reversible defects) and infarction (non-reversible defects), in evaluating myocardial function and developing information for use in patient management decisions. Technetium Tc 99m Sestamibi evaluation of myocardial ischemia can be accomplished with rest and cardiovascular stress techniques (e.g., exercise or pharmacologic stress in accordance with the pharmacologic stress agents labeling). It is usually not possible to determine the age of a myocardial infarction or to differentiate a recent myocardial infarction from ischemia. Breast Imaging: Kit for the preparation of Technetium Tc 99m Sestamibi Injection is indicated for planar imaging as a second line diagnostic drug after mammography to assist in the evaluation of breast lesions in patients with an abnormal mammogram or a palpable breast mass. Kit for the preparation of Technetium Tc 99m Sestamibi Injection is not indicated for breast cancer screening, to confirm the presence or absence of malignancy, and it is not an alternative to biopsy. Technetium Tc 99m Sestamibi, is a myocardial perfusion agent indicated for: detecting coronary artery disease by localizing myocardial ischemia (reversible defects) and infarction (non-reversible defects) ( 1 ) evaluating myocardial function and developing information for use in patient management decisions ( 1 )

2 DOSAGE AND ADMINISTRATION For Myocardial Imaging: The suggested dose range for I.V. administration of Technetium Tc 99m Sestamibi in a single dose to be employed in the average patient (70 kg) is 370 to 1110 MBq (10 to 30 mCi). For Breast Imaging: The recommended dose range for I.V. administration of Technetium Tc 99m Sestamibi is a single dose of 740 to 1110 MBq (20 to 30 mCi). For Myocardial Imaging: The suggested dose range for I.V. administration of Technetium Tc 99m Sestamibi in a single dose to be employed in the average patient (70 kg) is 370 to 1110 MBq (10 to 30 mCi) ( 2 ). For Breast Imaging: The recommended dose range for I.V. administration of Technetium Tc 99m Sestamibi is a single dose of 740 to 1110 MBq (20 to 30 mCi) ( 2 ). 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. Table 1. Radiation Absorbed Doses from Tc 99m Sestamibi Estimated Radiation Absorbed Dose REST STRESS 2.0 hour void 4.8 hour void 2.0 hour void 4.8 hour void Organ rads/30 mCi mGy/1110 MBq rads/30 mCi mGy/1110 MBq rads/30 mCi mGy/1110 MBq rads/30 mCi mGy/1110 MBq Breasts 0.2 2.0 0.2 1.9 0.2 2.0 0.2 1.8 Gallbladder Wall 2.0 20.0 2.0 20.0 2.8 28.9 2.8 27.8 Small Intestine 3.0 30.0 3.0 30.0 2.4 24.4 2.4 24.4 Upper Large Intestine Wall 5.4 55.5 5.4 55.5 4.5 44.4 4.5 44.4 Lower Large Intestine Wall 3.9 40.0 4.2 41.1 3.3 32.2 3.3 32.2 Stomach Wall 0.6 6.1 0.6 5.8 0.6 5.3 0.5 5.2 Heart Wall 0.5 5.1 0.5 4.9 0.5 5.6 0.5 5.3 Kidneys 2.0 20.0 2.0 20.0 1.7 16.7 1.7 16.7 Liver 0.6 5.8 0.6 5.7 0.4 4.2 0.4 4.1 Lungs 0.3 2.8 0.3 2.7 0.3 2.6 0.2 2.4 Bone Surfaces 0.7 6.8 0.7 6.4 0.6 6.2 0.6 6.0 Thyroid 0.7 7.0 0.7 2.4 0.3 2.7 0.2 2.4 Ovaries 1.5 15.5 1.6 15.5 1.2 12.2 1.3 13.3 Testes 0.3 3.4 0.4 3.9 0.3 3.1 0.3 3.4 Red Marrow 0.5 5.1 0.5 5.0 0.5 4.6 0.5 4.4 Urinary Bladder Wall 2.0 20.0 4.2 41.1 1.5 15.5 3.0 30.0 Total Body 0.5 4.8 0.5 4.8 0.4 4.2 0.4 4.2 Radiation dosimetry calculations performed by Radiation Internal Dose Information Center, Oak Ridge Institute for Science and Education, PO Box 117, Oak Ridge, TN 37831-0117. 2.3 Instructions for Preparation Preparation of the Technetium Tc 99m Sestamibi from the Kit for the Preparation of Technetium Tc 99m Sestamibi is done by the following aseptic procedure: General Procedure: a. 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. b. 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. Boiling Water Bath Procedure: c. Place the vial in a suitable radiation shield with a fitted radiation cap. d. With a sterile shielded syringe, aseptically obtain additive-free, sterile, non-pyrogenic Sodium Pertechnetate Tc 99m Injection [925 to 5550 MBq, (25 to 150 mCi)] in approximately 1 to 3 mL. e. 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. f. Shake vigorously, about 5 to 10 quick upward-downward motions. g. 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. h. Remove the vial from the water bath, place in the lead shield and allow to cool for fifteen (15) minutes. i. Using proper shielding, the vial contents should be visually inspected. Use only if

6 ADVERSE REACTIONS Adverse events were evaluated in 3741 adults who were evaluated in clinical studies. Of these patients, 3068 (77% men, 22% women, and 0.7 % of the patients' genders were not recorded) were in cardiac clinical trials and 673 (100% women) in breast imaging trials. Cases of angina, chest pain, and death have occurred [ see Warning and Precautions ( 5.1 ) ]. Adverse events reported at a rate of 0.5% or greater after receiving Technetium Tc 99m Sestamibi administration are shown in the following table: Table 2. Selected Adverse Events Reported in > 0.5 % of Patients Who Received Technetium Tc 99m Sestamibi in Either Breast or Cardiac Clinical Studies* Body System Breast Studies Cardiac Studies Women n = 673 Women n = 685 Men n = 2361 Total n = 3046 Body as a Whole 21 (3.1 %) 6 (0.9 %) 17 (0.7 %) 23 (0.8 %) Headache 11 (1.6 %) 2 (0.3 %) 4 (0.2 %) 6 (0.2 %) Cardiovascular 9 (1.3 %) 24 (3.5 %) 75 (3.2 %) 99 (3.3 %) Chest Pain/Angina 0 (0 %) 18 (2.6 %) 46 (1.9 %) 64 (2.1 %) ST Segment Changes 0 (0 %) 11 (1.6 %) 29 (1.2 %) 40 (1.3 %) Digestive System 8 (1.2 %) 4 (0.6 %) 9 (0.4 %) 13 (0.4 %) Nausea 4 (0.6 %) 1 (0.1 %) 2 (0.1 %) 3 (0.1 %) Special Senses 132 (19.6 %) 62 (9.1 %) 160 (6.8 %) 222 (7.3 %) Taste Perversion 129 (19.2 %) 60 (8.8 %) 157 (6.6 %) 217 (7.1 %) Parosmia 8 (1.2 %) 6 (0.9 %) 10 (0.4 %) 16 (0.5 %) * Excludes the 22 patients whose gender was not recorded. In the clinical studies for breast imaging, breast pain was reported in 12 (1.7 %) of the patients. In 11 of these patients the pain appears to be associated with biopsy/surgical procedures. The following adverse reactions have been reported in ≤ 0.5% of patients: signs and symptoms consistent with seizure occurring shortly after administration of the agent; transient arthritis; angioedema, arrhythmia, dizziness, syncope, abdominal pain, vomiting, and severe hypersensitivity characterized by dyspnea, hypotension, bradycardia, asthenia, and vomiting within two hours after a second injection of Technetium Tc 99m Sestamibi. A few cases of flushing, edema, injection site inflammation, dry mouth, fever, pruritis, rash, urticaria and fatigue have also been attributed to administration of the agent. The following adverse reactions have been reported in ≤ 0.5 % of patients: signs and symptoms consistent with seizure occurring shortly after administration of the agent; transient arthritis; angioedema, arrhythmia, dizziness, syncope, abdominal pain, vomiting, and severe hypersensitivity characterized by dyspnea, hypotension, bradycardia, asthenia, and vomiting within two hours after a second injection of Technetium Tc 99m Sestamibi. A few cases of flushing, edema, injection site inflammation, dry mouth, fever, pruritis, rash, urticaria and fatigue have also been attributed to administration of the agent ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Jubilant DraxImage Inc. at 1-888-633-5343or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

7 DRUG INTERACTIONS Specific drug-drug interactions have not been studied. Specific drug-drug interactions have not been studied ( 7 ).