Technetium

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 )

DOSAGE AND ADMINISTRATION Radiation Safety – Drug Handling After radiolabeling of Technescan PYP, the reaction vial contains Technetium Tc 99m Pyrophosphate Injection. Handle Technetium Tc 99m Pyrophosphate Injection with appropriate safety measures to minimize radiation exposure. (See PRECAUTIONS, General .) Use waterproof gloves, effective radiation shielding, and other appropriate safety measures when preparing and handling Technetium Tc 99m Pyrophosphate Injection. Radiopharmaceuticals should be used by or under the control of healthcare providers who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. Recommended Dosage, Administration, and Imaging Instructions for Skeletal and Cardiac Imaging Dosing and Administration Instructions The recommended activity of Technetium Tc 99m Pyrophosphate Injection for each type of imaging is presented in Table 4. Administer Technetium Tc 99m Pyrophosphate Injection intravenously over 10 seconds to 20 seconds. Measure the patient dose with a dose calibrator immediately before administration. If not contraindicated by patient’s condition, encourage patients to drink fluids before and after administration and void as often as possible to reduce unnecessary radiation exposure. For radiolabeling instructions, see Directions for Drug Preparation , Procedure for the Preparation of Technetium Tc 99m Pyrophosphate Injection. Table 4. Recommended Administered Activity of Technetium Tc 99m Pyrophosphate Injection for Skeletal and Cardiac Imaging in Adults Indication Activity of Technetium Tc 99m Pyrophosphate Fraction of Vial Contents Required for Pyrophosphate Skeletal Imaging 185 MBq to 555 MBq (5 mCi to 15 mCi) 0.07 to 0.91 Cardiac Imaging 370 MBq to 555 MBq (10 mCi to 15 mCi) 0.26 to 0.45 Skeletal Imaging Begin imaging 1 hour to 6 hours following administration. Cardiac Imaging The patient's cardiac condition should be stable before beginning the cardiac imaging procedure. Begin imaging 60 minutes to 90 minutes following administration. The acute myocardial infarct can be visualized from 24 hours to 9 days following onset of symptoms, with maximum localization at 48 to 72 hours. Cardiac imaging should be done with a gamma scintillation camera. It is recommended that images include anterior, left anterior oblique, and left lateral projections. Interference from chest wall lesions such as breast tumors and healing rib fractures can be minimized by employing the three recommended projections. Recommended Dosage, Administration, and Imaging Instructions for Gated Cardiac Blood Pool and Gastrointestinal Bleed Imaging Dose The recommended dose of Technescan PYP reconstituted in 0.9% sodium chloride injection for gated cardiac blood pool and gastrointestinal bleed imaging in adults is 1 mL, followed by 555 MBq to 740 MBq (15 mCi to 20 mCi) of sodium pertechnetate Tc 99m injection. Administration Instructions for In Vivo RBC Labeling Method a. Reconstitute Technescan PYP with 0.9% sodium chloride injection. (See Directions for Drug Preparation , Procedure for the Reconstitution of Technescan PYP.) b. Administer the patient dose of reconstituted Technescan PYP intravenously by direct venipuncture. Do not use heparinized catheters. (See WARNINGS .) c. Wait 15 minutes to 30 minutes. d. Administer sodium pertechnetate Tc 99m injection intravenously. Administration Instructions for Modified In Vivo/In Vitro RBC Labeling Method Using ACD a. Reconstitute Technescan PYP with 0.9% sodium chloride injection. (See Directions for Drug Preparation , Procedure for the Reconstitution of Technescan PYP.) b. Administer the patient dose of reconstituted Technescan PYP intravenously by direct venipuncture. Do not use heparinized catheters. (See WARNINGS .) c. Insert an intravenous line with a 3-way stopcock in a large peripheral vein and maintain the line with a continuous drip of 0.9% sodium chloride injection. d. 30 minutes post-injection: Clear the line by withdrawing and discarding approximately 5 mL of blood. Then draw approximately 5 mL of blood into a syringe containing 1 mL preservative-free acid-citrate-dextrose (ACD) and 555 MBq to 740 MBq (15 mCi to 20 mCi) of sodium pertechnetate Tc 99m injection. Turn the stopcock, flush the line, and adjust the flow of 0.9% sodium chloride injection. e. Gently rotate syringe to mix and incubate at room temperature for 10 minutes. f. Inject the mixture via the 3-way stopcock. Administration Instructions for Modified In Vivo/In Vitro RBC Labeling Method Using Heparin a. Reconstitute Technescan PYP with 0.9% sodium chloride injection. (See Directions for Drug Preparation , Procedure for the Reconstitution of Technescan PYP.) b. Administer the patient dose of reconstituted Technescan PYP intravenously by direct venipuncture. Do not use heparinized catheters. (See WARNINGS .) c. Insert an infusion set fitted with a 3-way stopcock in a large peripheral vein, and heparinize the intravenous line with 0.9% sodium chloride injection containing 5 units/mL to 10 units/mL of preservative-free heparin. d. Thirty minutes after Technescan PYP injection, draw 3 mL of blood into a syringe containing 555 MBq to 740 MBq (15 mCi to 20 mCi) of sodium pertechnetate Tc 99m injection. Anticoagulation of the blood is provided by residual heparin in the intravenous line. e. Gently rotate the syringe to mix and incubate at room temperature for 10 minutes. f. Inject the mixture via the 3-way stopcock. Gated Cardiac Blood Pool Imaging Begin cardiac imaging 10 minutes following the administration of sodium pertechnetate Tc 99m injection (in vivo method) or Tc 99m labeled red blood cells (modified in vivo/in vitro method) utilizing a scintillation camera interfaced to an electrocardiographic gating device. Gastrointestinal Bleed Imaging The imaging of gastrointestinal bleeding is dependent on factors such as the region of imaging, rate and volume of the bleed, efficacy of labeling of the red blood cells, and timeliness of imaging. Acquire sequential images over a period of time until a positive image is obtained or clinical conditions warrant the discontinuance of the procedure. The period of time for collecting the images may range up to 36 hours. Directions for Drug Preparation Procedural Precautions • The contents of the Technescan PYP reaction vial may be used for the preparation of Technetium Tc 99m Pyrophosphate Injection. Technescan PYP may also be reconstituted with preservative-free 0.9% sodium chloride injection and injected intravenously prior to labeling of red blood cells with sodium pertechnetate Tc 99m injection using either the in vivo or modified in vivo/in vitro method. • The components of the kit are sterile and non-pyrogenic. It is essential that the user follow the directions carefully and adhere to strict aseptic procedures during preparation. • Wear waterproof gloves during the entire preparation procedure and during subsequent patient dose withdrawals from the reaction vial. • Make all withdrawals and administration of sodium pertechnetate Tc 99m injection with an adequately shielded syringe. • Keep the prepared Technetium Tc 99m Pyrophosphate Injection in the lead shield described below (with cap in place) during the useful life of the radioactive preparation. Make all withdrawals and administration of the Technetium Tc 99m Pyrophosphate Injection with an adequately shielded syringe. • Any sodium pertechnetate Tc 99m injection that contains an oxidizing agent is not suitable for use in the preparation of Technetium Tc 99m Pyrophosphate Injection. Procedure for the Preparation of Technetium Tc 99m Pyrophosphate Injection 1. Remove a Technescan PYP reaction vial from the refrigerator and allow the vial contents to come to room temperature, 20°C to 25°C (68°F to 77°F), for approximately 5 minutes. 2. Attach the radioassay

WARNINGS Image interpretation errors can occur. As an adjunct in the diagnosis of confirmed myocardial infarction (ECG and serum enzymes positive), the estimate of false negative image interpretations was 6%. False negative image interpretations can occur if made too early in the evolutionary phase of the infarct or too late in the resolution phase. In a study involving 22 patients in whom ECG was positive and serum enzymes questionable or negative, but in whom the final diagnosis of acute myocardial infarction was made, the estimates of false negative and false positive image interpretations were 23% and 9%, respectively. False positive image interpretations have been reported following coronary artery bypass graft surgery and in unstable angina pectoris, old myocardial infarcts, and cardiac contusions. Technetium Tc 99m pyrophosphate may impair brain imaging with sodium pertechnetate Tc 99m and result in false positive or false negative image interpretation. It is recommended, where feasible, that brain imaging precede skeletal imaging procedures. Gated cardiac blood pool and gastrointestinal bleed imaging may be impaired in patients receiving sodium heparin for anticoagulant therapy. This is characterized by a reduction in the amount of injected radioactivity remaining in the blood pool. Avoid heparinized catheter systems for administration of Technescan PYP. The biodistribution of technetium Tc 99m pyrophosphate may be altered in the presence of high levels of certain cations (iron, calcium, and aluminum). This may result in reduced uptake of radionuclide in the skeleton and increased extraosseal uptake, which may potentially degrade imaging quality. High levels of these cations may be caused by concomitant medications or medical conditions (e.g., iron overload, hypercalcemia, etc.). Most cases are observed after iron infusion. (See PRECAUTIONS, Drug Interactions .)

CONTRAINDICATIONS None known. None known ( 4 ).

Drug Interactions The biodistribution of technetium Tc 99m pyrophosphate may be altered in the presence of high levels of certain cations (iron, calcium, and aluminum). This may result in reduced uptake of radionuclide in the skeleton and increased extraosseal uptake, which may potentially degrade imaging quality. In patients with high levels of these cations caused by concomitant medications, particularly patients receiving iron infusions, consider performing an imaging study with technetium Tc 99m pyrophosphate injection once the cation levels have normalized (e.g., after 3 to 5 half-lives of the cation). (See WARNINGS .)

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 .

CLINICAL PHARMACOLOGY General When technetium Tc99m pertechnetate is added to exametazime in the presence of stannous reductant, a lipophilic technetium Tc99m complex is formed. This lipophilic complex is the active moiety. It converts at approximately 12%/hour to less lipophilic species. When the secondary complex is separated from the lipophilic species, it is unable to cross the blood-brain-barrier. The useful life of the reconstituted agent is limited to 30 minutes. Pharmacokinetics Studies in normal volunteers have shown that the technetium Tc99m complex of the RR,SS(d,l) diastereoisomer of exametazime is rapidly cleared from the blood after intravenous injection. Uptake in the brain reaches a maximum of 3.5-7.0% of the injected dose within one minute of injection. Up to 15% of the activity is eliminated from the brain by 2 minutes post injection, after which little activity is lost for the following 24 hours except by physical decay of technetium Tc99m. The activity not associated with the brain is widely distributed throughout the body, particularly in muscle and soft tissue. About 30% of the injected dose is found in the gastrointestinal tract immediately after injection and about 50% of this is excreted through the intestinal tract over 48 hours. Also, about 40% of the injected dose is excreted through the kidneys and urine over the 48 hours after injection. Leukocyte The lipophilic Tc99m exametazime complex is taken up by leukocytes, and selectively retained in neutrophils. Label elution rate is up to 10% in the first hour. Pharmacodynamics Tc99m-labeled leukocyte: Based upon in vivo recovery and very low lung and liver uptake, the labeled leukocytes are still functional. Following reinjection of the Tc99m labeled leukocytes the circulating granulocyte activity as a percentage of labeled granulocyte activity at 40 minutes after injection gave a mean of 37% (range 10-47%). During the first hour following injection of Tc99m labeled leukocytes, activity is seen in the lungs, liver, spleen, blood pool, bone marrow and the bladder. The kidneys (parenchyma and/or renal pelvis) and gall bladder may also be visualized. Over the first 1-6 hours, the Tc99m is visualized in the bowel. At 24 hours post-injection substantial colonic activity is seen. The normal areas visualized in earlier scans are still visible.