Kit for the Preparation of Technetium Tc99m Sestamibi

1 INDICATIONS AND USAGE Myocardial Imaging: 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 agent’s 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: Technetium Tc 99m Sestamibi 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. Technetium Tc 99m Sestamibi 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: ( 1 ) • 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 Tc99m Sestamibi in a single dose to be employed in the average patient (70 Kg) is 370-1110 MBq (10-30 mCi). For Breast Imaging: The recommended dose range for I.V. administration of Technetium Tc99m Sestamibi is a single dose of 740-1110 MBq (20 - 30 mCi). For Myocardial Imaging: The suggested dose range for I.V. administration of Technetium Tc99m Sestamibi in a single dose to be employed in the average patient (70 Kg) is 370-1110 MBq (10-30 mCi). For Breast Imaging: The recommended dose range for I.V. administration of Technetium Tc99m Sestamibi is a single dose of 740-1110 MBq (20 - 30 mCi). 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 Tc99m 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 Tc99m Sestamibi injected intravenously are shown in Table 1.0. Table 1.0. Radiation Absorbed Doses from Tc99m Sestamibi Estimated Radiation Absorbed Dose REST 2.0 hour void 4.8 hour void Organ rads/30 mCi mGy/1110 MBq rads/30 mCi mGy/1110 MBq Breasts 0.2 2.0 0.2 1.9 Gallbladder Wall 2.0 20.0 2.0 20.0 Small Intestine 3.0 30.0 3.0 30.0 Upper Large Intestine Wall 5.4 55.5 5.4 55.5 Lower Large Intestine Wall 3.9 40.0 4.2 41.1 Stomach Wall 0.6 6.1 0.6 5.8 Heart Wall 0.5 5.1 0.5 4.9 Kidneys 2.0 20.0 2.0 20.0 Liver 0.6 5.8 0.6 5.7 Lungs 0.3 2.8 0.3 2.7 Bone Surfaces 0.7 6.8 0.7 6.4 Thyroid 0.7 7.0 0.7 7.0 Ovaries 1.5 15.5 1.6 15.5 Testes 0.3 3.4 0.4 3.9 Red Marrow 0.5 5.1 0.5 5.0 Urinary Bladder Wall 2.0 20.0 4.2 41.1 Total Body 0.5 4.8 0.5 4.8 STRESS 2.0 hour void 4.8 hour void Organ rads/30 mCi mGy/1110 MBq rads/30 mCi mGy/1110 MBq Breasts 0.2 2.0 0.2 1.8 Gallbladder Wall 2.8 28.9 2.8 27.8 Small Intestine 2.4 24.4 2.4 24.4 Upper Large Intestine Wall 4.5 44.4 4.5 44.4 Lower Large Intestine Wall 3.3 32.2 3.3 32.2 Stomach Wall 0.6 5.3 0.5 5.2 Heart Wall 0.5 5.6 0.5 5.3 Kidneys 1.7 16.7 1.7 16.7 Liver 0.4 4.2 0.4 4.1 Lungs 0.3 2.6 0.2 2.4 Bone Surfaces 0.6 6.2 0.6 6.0 Thyroid 0.3 2.7 0.2 2.4 Ovaries 1.2 12.2 1.3 13.3 Testes 0.3 3.1 0.3 3.4 Red Marrow 0.5 4.6 0.5 4.4 Urinary Bladder Wall 1.5 15.5 3.0 30.0 Total Body 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 Tc99m Sestamibi is done by the following aseptic procedure: General Procedure: a. Prior to adding the Sodium Pertechnetate Tc99m 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. Boilin …

3. DOSAGE FORMS AND STRENGTHS Kit for the Preparation of Technetium Tc99m Sestamibi for Injection is supplied as a lyophilized mixture in a 5 mL vial. Kit for the Preparation of Technetium Tc99m Sestamibi for Injection is supplied as a lyophilized mixture in a 5 mL vial.

4 CONTRAINDICATIONS None known. • None known. ( 4 )

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 Warnings and Precautions ( 5 ) ]. 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 Excludes the 22 patients whose genders were not recorded. Body System Breast Studies Cardiac Studies Women Women Men Total n = 673 n = 685 n = 2361 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%) 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, pruritus, 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, pruritus, rash, urticaria and fatigue have also been attributed to administration of the agent ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Cardinal Health at 1-800-618-2768 or 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 ).

8. USE IN SPECIFIC POPULATIONS In one study of 46 subjects who received Technetium Tc99m Sestamibi administration, the radioactivity in both children and adolescents exhibited blood PK profiles similar to those previously reported in adults. Lactation: Interruption of breastfeeding after exposure to Technetium Tc99m Sestamibi is not necessary, however, a lactating woman should be advised to consider restricting 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. ( 8.2 ) 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 ima …

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 Tl-201. Scintigraphic images obtained in humans after the intravenous administration of the drug have been comparable to those obtained with thallous chloride Tl-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.

11 DESCRIPTION Each 5 mL vial contains a sterile, non-pyrogenic, lyophilized mixture of: • Tetrakis (2-methoxy isobutyl isonitrile) Copper (I) tetrafluoroborate - 1.0 mg • Sodium Citrate Dihydrate - 2.6 mg • L-Cysteine Hydrochloride Monohydrate - 1.0 mg • Mannitol - 20 mg • Stannous Chloride, Dihydrate, minimum (SnCl 2 •2H 2 O) - 0.025 mg • Stannous Chloride, Dihydrate (SnCl 2 •2H 2 O) - 0.075 mg • Tin Chloride (stannous and stannic) Dihydrate, maximum (as SnCl 2 •2H 2 O) - 0.086 mg Prior to lyophilization the pH is 5.3 to 5.9. The contents of the vial are lyophilized and stored under nitrogen. This drug is administered by intravenous injection for diagnostic use after reconstitution with sterile, non-pyrogenic, oxidant-free Sodium Pertechnetate Tc 99m Injection. The pH of the reconstituted product is 5.5 (5.0–6.0). No bacteriostatic preservative is present. The precise structure of the technetium complex is Tc 99m[MIBI] 6 + where MIBI is 2-methoxy isobutyl isonitrile. Tetrakis (2-methoxy isobutyl isonitrile) Copper (I) tetrafluoroborate has the following structural formula: 11.1 Physical Characteristics Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours 2 . Photons that are useful for detection and imaging studies are listed below in Table 3 . Table 3 Principal Radiation Emission Data Radiation Mean %/Disintegration Mean Energy (KeV) Gamma -2 89.07 140.5 2 Kocher, 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 (0.78R/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. Table 4 Radiation Attenuation by Lead Shielding Shield Thickness (Pb) cm Coefficient of Attenuation 0.017 0.5 0.08 10 –1 0.16 10 –2 0.25 10 –3 0.33 10 –4 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 . Table 5 Physical Decay Chart; Tc 99m Half-Life 6.02 Hours Hours Fraction Remaining Hours Fraction Remaining 0 Calibration Time 1.000 7 0.447 1 0.891 8 0.398 2 0.794 9 0.355 3 0.708 10 0.316 4 0.631 11 0.282 5 0.562 12 0.251 6 0.501 Structural Formula

10. OVERDOSAGE The clinical consequences of overdosing with Technetium Tc99m Sestamibi are not known.

16. HOW SUPPLIED/STORAGE AND HANDLING Kit for the Preparation of Technetium Tc99m Sestamibi for Injection is supplied as a 5 mL vial in a kit of twenty (20) vials (NDC # 11994-003-20), sterile and non-pyrogenic. The patient dose should be measured by a suitable radioactivity calibration system immediately prior to patient administration. Radiochemical purity should be checked prior to patient administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Store at 15-25°C (59-77°F) before and after reconstitution. Prior to lyophilization the pH is between 5.3 and 5.9. The contents of the vial are lyophilized and stored under nitrogen. Store at 15-25°C (59-77°F) before and after reconstitution. Technetium Tc99m Sestamibi contains no preservatives. Included in each twenty (20) vial kit is one (1) package insert, twenty four (24) vial shield labels and twenty four (24) radiation warning labels. This reagent kit is approved for distribution to persons licensed pursuant to the Code of Massachusetts Regulations 105 CMR 120.500 for the uses listed in 105 CMR 120.547 or 120.552, or under equivalent regulations of the U.S. Nuclear Regulatory Commission, Agreement States or Licensing States.