Technetium Tc 99m Sestamibi

1. INDICATIONS AND USAGE Myocardial Imaging: Kit for the Preparation of Technetium Tc99m 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 Tc99m 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: Kit for the Preparation of Technetium Tc99m 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 Tc99m 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 Tc99m Sestamibi is a myocardial perfusion agent indicated for: ( 1 ) detecting coronary artery disease by localizing myocardial ischemia (reversible defects) and infarction (non-reversible defects) evaluating myocardial function and developing information for use in patient management decisions

3. DOSAGE FORMS AND STRENGTHS Kit for the Preparation of Technetium Tc99m Sestamibi Injection is supplied as a lyophilized mixture in a 10 mL vial. Kit for the Preparation of Technetium Tc99m Sestamibi Injection is supplied as a lyophilized mixture in a 10 mL vial. ( 3 )

4. CONTRAINDICATIONS None known. None known.

5. WARNINGS AND PRECAUTIONS Pharmacologic induction of cardiovascular stress may be associated with serious adverse events such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction and cerebrovascular events. Technetium Tc99m 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 Technetium Tc99m Sestamibi imaging. Caution should be exercised and emergency equipment should be available when administering Technetium Tc99m Sestamibi. Before administering Technetium Tc99m Sestamibi patients should be asked about the possibility of allergic reactions to either drug. The contents of the vial are intended only for use in the preparation of Technetium Tc99m Sestamibi and are not to be administered directly to the patient without first undergoing the preparative procedure.

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 Tc99m 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 Tc99m 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 Tc99m Sestamibi imaging. Patients who receive Technetium Tc99m 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 Tc99m Sestamibi. Also, before administering Technetium Tc99m 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 Tc99m 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 Tc99m 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 Tc99m labeling reactions depend on maintaining the stannous ion in the reduced state. Hence, Sodium Pertechnetate Tc99m Injection containing oxidants should not be used. Technetium Tc99m 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%

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 Tc99m 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 Tc99m 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 Tc99m Sestamibi imaging. Patients who receive Technetium Tc99m 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 Tc99m Sestamibi. Also, before administering Technetium Tc99m Sestamibi Injection, patients should be asked about the possibility of allergic reactions to the drug.

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 Section 5 ). Adverse events reported at a rate of 0.5% or greater after receiving Technetium Tc99m Sestamibi administration are shown in the following table: 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 Tc99m 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 Tc99m 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. To report SUSPECTED ADVERSE REACTIONS, contact Curium US LLC at 1-866-789-2211 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Table

2.0 Selected Adverse Events Reported in > 0.5% of Patients Who Received Technetium Tc99m Sestamibi in Either Breast or Cardiac Clinical Studies*

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

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 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 Tc99m Sestamibi in adults. Two of the 609 had a serious adverse event: one patient received a Technetium Tc99m 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 Technetium Tc99m Sestamibi for myocardial imaging, 693 patients were 65 or older and 121 were 75 or older. Of 673 patients in clinical studies of Technetium Tc99m Sestamibi for breast imaging, 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.

Technetium Tc99m Sestamibi is a cationic Tc99m 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 Tc99m 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 Tc99m Sestamibi localization in various types of breast tissue (e.g., benign, inflammatory, malignant, fibrous) has not been established.