CardioGen-82

1 INDICATIONS AND USAGE CardioGen-82, used to produce Rubidium Chloride Rb 82 Injection, is indicated for positron emission tomography (PET) of the myocardium under rest or pharmacologic stress conditions to evaluate regional myocardial perfusion in adult patients with suspected or existing coronary artery disease. CardioGen-82, used to produce Rubidium Chloride Rb 82 Injection, is a radioactive diagnostic agent indicated for positron emission tomography (PET) of the myocardium under rest or pharmacologic stress conditions to evaluate regional myocardial perfusion in adult patients with suspected or existing coronary artery disease. ( 1 )

2 DOSAGE AND ADMINISTRATION Dosing: 10 MBq/kg to 30 MBq/kg actual body weight (0.27 mCi/kg to 0.81 mCi/kg) per rest or stress component of a procedure via intravenous infusion at 50 mL/minute or 20 mL/minute. ( 2.2 ) Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure. ( 2.2 ) The minimum interval between the rest and stress doses is 10 minutes to allow sufficient Rb 82 decay. ( 2.2 ) Start image acquisition 60 seconds to 90 seconds after completion of the infusion; if a longer circulation time is anticipated, wait for 120 seconds. Image acquisition is 5 minutes long. ( 2.3 ) For radiation safety, infusion system, elution instruction, eluate testing, dose delivery, and expiration limits of CardioGen-82, and radiation dosimetry see full prescribing information. ( 2.1 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) 2.1 Radiation Safety - Drug Handling CardioGen-82, when eluted with additive-free 0.9% Sodium Chloride Injection, produces Rubidium Chloride Rb 82 Injection. Handle CardioGen-82, Rubidium Chloride Rb 82 Injection, and Infusion Systems with appropriate safety measures to minimize radiation exposure. Wear waterproof gloves and effective shielding throughout the entire preparation and handling [See Warnings and Precautions ( 5.4 )]. Limit the use of radiopharmaceuticals to 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 government agency authorized to license the use of radionuclides. 2.2 Dosing and Administration of Rubidium Chloride Rb 82 Injection Dosing The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in adults is 10 MBq/kg to 30 MBq/kg actual body weight (0.27 mCi/kg to 0.81 mCi/kg) administered by intravenous infusion at 50 mL/minute or 20 mL/minute through a catheter inserted into a large peripheral vein. Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure. Administration Instructions Observe aseptic techniques in all drug handling and administration. Use CardioGen-82 with the CardioGen-82 Model 1700 Infusion System to elute and administer Rubidium Chloride Rb 82 Injection. Use the lowest dose necessary, consistent with the goal of as low as reasonably achievable (ALARA), to obtain adequate cardiac visualization based on patient body weight and the imaging equipment and acquisition methodology used to perform the procedure. For example, 3D image acquisition may require doses at the lower end of the recommended range, compared to 2D imaging. Administer two single doses to complete rest and stress myocardial perfusion imaging (MPI) [see Dosage and Administration ( 2.3 )] . The minimum interval between the rest and stress doses is 10 minutes to allow sufficient Rb 82 decay. Instruct patients to void as soon as a study is completed and as often as possible thereafter for at least one hour [see Warnings and Precautions ( 5.4 )] . 2.3 Image Acquisition Instructions Rest Imaging Administer a single dose of Rubidium Chloride Rb 82 Injection. Start imaging 60 seconds to 90 seconds after completion of the first dose infusion and acquire images for 5 minutes. Stress Imaging Begin the study at least 10 minutes after completion of the resting dose infusion, to allow for sufficient Rb 82 decay. Administer a pharmacologic stress agent in accordance with its prescribing information. After the administration of the pharmacologic stress agent, administer the second dose of Rubidium Chloride Rb 82 Injection at the time interval according to the prescribing information of the pharmacologic stress agent. Start imaging 60 seconds to 90 seconds after completion of the second dose infusion and acquire images for 5 minutes. Rest and Stress Imaging If a longer circulation time is anticipated (e.g., in a patient with severe left ventricular dysfunction), start imaging 120 seconds after the dose. Acquisition may be started immediately post-injection if dynamic imaging is needed. 2.4 Infusion System Use CardioGen-82 only with the CardioGen-82 Infusion System Model 1700, which is specifically designed for use with the generator and capable of accurate measurement and delivery of doses of Rubidium Chloride Rb 82 Injection. The accuracy of the CardioGen-82 Infusion System Model 1700 for measuring Rubidium Rb 82 Chloride Injection is as follows: For doses of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi), the system provides an accuracy of ± 10%. For doses of 370 MBq to 1,110 MBq (10 mCi to 30 mCi), the system provides an accuracy of ± 15%. Follow instructions in the CardioGen-82 Infusion System Model 1700 Operator’s Manual for the setup and administration of Rubidium Chloride Rb 82 Injection. 2.5 Directions for Eluting Rubidium Chloride Rb 82 Injection Use only additive-free 0.9% Sodium Chloride Injection to elute the generator [see Warnings and Precautions ( 5.1 )] . Prepare the 0.9% Sodium Chloride Injection for use with the Saline Tag. Prepare the intravenous port in accordance with the approved prescribing information of the 0.9% Sodium Chloride Injection. The intravenous administration port of the 0.9% Sodium Chloride Injection container must be penetrated only one time. Strap the saline tag provided with the CardioGen-82 Infusion System on the additive-free 0.9% Sodium Chloride Injection container and install on the CardioGen-82 Infusion System. Once the container port closure is penetrated, it should remain installed on the CardioGen-82 Infusion System for its entire period of use. A maximum of 12 hours from the initial port closure penetration is permitted, after which the bag must be replaced for the next patient. Allow at least 10 minutes between elutions for regeneration of Rb 82. The system automatically discards the first 50 mL of eluate each day the generator is eluted and records and saves all eluate volumes (all flushing, quality control (QC) testing, and patient infusions), representing the cumulative volume of eluate each day the generator is eluted. Perform eluate testing according to the Eluate Testing Protocol [see Dosage and Administration ( 2.6 )]. Stop using the generator when the expiration limits are reached [see Dosage and Administration ( 2.7 )]. The maximum available activity of Rb 82 (dose delivery limit) will decrease as the generator ages. See Table 1 for the estimated maximum available Rb 82 activity as a function of generator age for a generator with an initial 100 mCi of Sr 82 [see Dosage and Administration ( 2.8 )]. 2.6 Eluate Testing Protocol for Infusion System Model 1700 General Precautions Use only additive-free 0.9% Sodium Chloride Injection for all elutions [see Warnings and Precautions ( 5.1 )] . Observe aseptic technique throughout. Follow all instructions in the CardioGen-82 Infusion System Model 1700 Operator’s Manual for performing all eluate testing as described. Mandatory Eluate Testing Perform Mandatory Eluate Testing to determine Rb 82, Sr 82, and Sr 85 levels (see Daily Quality Control Procedure) : Daily – Before administering Rubidium Chloride Rb 82 Injection to the first patient each day. Repeat as indicated after an Alert Limit has been detected. Alert Limits and System Response : The CardioGen-82 Infusion System Model 1700 will automatically indicate when any of the following Alert Limits have been reached: 14 L total elution volume has passed through the generator column, or Sr 82 level reaches 0.002 microCi per mCi Rb 82, or Sr 85 level reaches 0.02 microCi per mCi Rb 82. Once an Alert Limit has been reached, the system will require additional eluate testing at intervals determined by the day’s elution volume and enforced by the system software. Specifically, the infusion system will require the user to perform additional eluate testing after each 750 mL of elution volume when any Alert Limit parameter has been reached. Infusion System Calibration Before administering Rubidium Chloride Rb 82 Injection to the first patient, perform the Rubidium Chloride Rb 82 Injection Dose Calibration using an external dose calibrator at the following times (see Calibration Procedure) : After installation of a new generator After installation of a new CardioGen-82 Accessory Package, Item # 001710 Every 14 days Calibration Procedure Set a dose calibrator for Rb 82 as recommended by the manufacturer. Obtain the reading from the instrument in millicuries. Following the prompts in the Graphical User Interface (GUI) for the CardioGen-82 Infusion System Model 1700, elute the generator with additive-free 0.9% Sodium Chloride Injection at a rate of 50 mL/min and collect the eluate in the stoppered vial specifically provided for use with the CardioGen-82 Infusion System Model 1700 (alternative vials, glass or plastic are not suitable). Note the exact time of end of elution (EOE). Using the external dose calibrator, assay the eluate at exactly 2:30, 3:45, or 5:00 minutes after EOE. Following the prompts in the GUI for the CardioGen-82 Infusion System Model 1700, enter the Rb 82 reading from the dose calibrator and the time since EOE. The infusion system software will automatically calculate the Calibration Ratio. If the ratio is within +/- 2% (0.98 to 1.02), the infusion system will allow acceptance of the calibration factor that was used for the elution. If the ratio is not within +/- 2% (0.98 to 1.02), the system requires another calibration elution (steps 1 through 4). Repeat steps 1 through 4 for a flow rate of 20 mL/min. Daily Quality Control Procedure Each day, before administering Rubidium Chloride Rb 82 Injection, perform the following testing: Place the stoppered vial into the Sr detector well. Use only the stoppered vial provided for use with the CardioGen-82 Infusion System Model 1700. Following the GUI prompts, initiate the Daily Quality Control workflow. The infusion system will automatically perform the Sr Detector Background Reading. The infusion system will automatically perform the Generator Column Wash. Strontium Level Test and Dose Constancy: The infusion system will elute the generator with 50 mL of additive-free 0.9% Sodium Chloride Injection at a rate of 50 mL/min into the stoppered vial. The Sr detector measures the Rb 82 and strontium in the 50 mL elution. The infusion system software will automatically calculate the Sr 82 and Sr 85 levels on the day (post calibration) of the measurement using the ratio of Sr 85/Sr 82 on the day of calibration provided on the generator label, and using the full exponential decay calculation for each, accounting for the generator’s age. Using the Rb 82 and strontium measurements, the infusion system software will automatically calculate microCi Sr 82/mCi Rb 82 and microCi Sr 85/mCi Rb 82. The GUI will automatically indicate if the results exceed Alert or Expiration Limits. The infusion system software will automatically calculate Dose Constancy. Constancy Check of the Sr detector: The GUI will prompt the user to perform the constancy check of the Sr detector. Place the external constancy source in the detector well of the infusion system. The infusion system software will automatically calculate the constancy of the Sr detector versus the external constancy source when instructed. 2.7 Expiration Limits of CardioGen-82 The CardioGen-82 Infusion System Model 1700 software will automatically indicate and will stop use of CardioGen-82 once any one of the following Expiration Limits is reached. A total elution volume of 17 L has passed through the generator column 60 days post calibration date An eluate Sr 82 level of 0.01 microCi/mCi Rb 82 An eluate Sr 85 level of 0.1 microCi/mCi Rb 82 2.8 Dose Delivery Limit of CardioGen-82 The maximum available Rb 82 activity per elution (dose delivery limit) will decrease as the generator ages. Certain doses, including the maximum recommended dose of 2,220 MBq (60 mCi), may not be achievable for the entire shelf-life of the generator. Table 1 provides an estimate of the maximum available activity of Rb 82 as a function of generator age for a generator with an initial 100 mCi of Sr 82. Table 1. Maximum Available Rb 82 Activity Based on Generator Age 1 Generator Age (days) 2 Maximum Rb 82 Activity per Elution 0 to 17 60 mCi (2,220 MBq) 24 50 mCi (1,850 MBq) 32 40 mCi (1,480 MBq) 42 30 mCi (1,110 MBq) 57 20 mCi (740 MBq) 60 19 mCi (703 MBq) 1 Estimate is based on a 100 mCi (3,700 MBq) Sr 82 generator at calibration. 2 Generator age at which delivery limit is reached varies with generator activity at release. For example, a 90 mCi (3,330 MBq) generator and a 150 mCi (5,550 MBq) generator will reach a delivery limit <60 mCi at ≥ 14 days and ≥ 33 days, respectively. 2.9 Radiation Dosimetry The estimated absorbed radiation doses for Rb 82, Sr 82, and Sr 85 from an intravenous injection of Rubidium Chloride Rb 82 Injection are shown in Table 2. Table 2. Estimated Absorbed Radiation Dose Coefficient in Adults Organ a,b Rb 82 (Average for Rest and Stress) mrem/mCi (microSv/3.7MBq) c Sr 82 mrem/microCi (microSv/3.7kBq) c Sr 85 mrem/microCi (microSv/3.7kBq) c Adrenals 7.56 10.6 5.03 Bone – Osteogenic cells Bone Surface 1.86 ---- --- 107 --- 9.81 Brain 0.6 8.29 2.96 Breast 0.82 7.03 1.72 Gall Bladder Wall 3.17 8.47 2.82 Heart Wall 16.5 8.18 2.67 Kidneys 20.04 9.18 2.5 Liver 4.2 8.10 2.5 Lower Large Intestine Wall 2.84 51.8 5.14 Lungs d 10.7 8.25 2.84 Muscles 1.29 8.14 2.66 Ovaries 1.41 10.2 4.29 Pancreas 8.85 9.1 3.46 Red Marrow 1.19 91 9.84 Skin 1.14 7.03 1.75 Small Intestine 4.76 9.62 4.03 Spleen 6.61 8.1 2.54 Stomach 8.14 7.84 2.26 Testes 0.82 7.25 1.7 Thymus 1.49 7.84 2.33 Thyroid 6.11 8.07 2.57 Upper Large Intestine 5.94 23.7 3.62 Urinary Bladder Wall 1.61 21.9 2.9 Uterus 3.72 9.14 3.32 Total Body 1.77 Not calculated Not calculated Effective Dose e 4.74 f 23.4 4.03 a Rb 82 doses are averages of rest and stress dosimetry data. To calculate organ doses (mrem) from Rb 82, multiply the dose coefficient for each organ by the administered activity in mCi. b Sr 82 and Sr 85 doses are calculated using software package DCAL and ICRP dose coefficients. To calculate organ doses (mrem) attributable to Sr 82, and Sr 85, multiply the dose coefficients by the calculated amounts of strontium in microCi. c To convert to SI units, insert the dose coefficient into the formula in parentheses, e.g. for adrenals 7.56 mrem/mCi = 7.56 microSv/37 MBq = 2.04 x 10 -13 Sv/Bq. d Calculated from ICRP 66 e Calculated from ICRP 60 f Stress phase only

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Risk Associated with Pharmacological Stress: Pharmacologic induction of cardiovascular stress may cause serious adverse reactions such as myocardial infarction, arrhythmia, hypotension, broncho-constriction, and cerebrovascular events. Perform testing only in setting where cardiac resuscitation equipment and trained staff are readily available. ( 5.3 ) 5.1 High Level Radiation Exposure with Use of Incorrect Eluent Additives present in solutions (particularly calcium ions) used by mistake to elute CardioGen-82 expose patients to high levels of radiation by causing the release of large amounts of Sr 82 and Sr 85 into the eluate regardless of the generator’s age or prior use . When solutions containing calcium ions are used, high levels of radioactivity are present in any subsequent eluate even with the use of additive-free 0.9% Sodium Chloride Injection. Use only additive-free 0.9% Sodium Chloride Injection to elute CardioGen-82. If an incorrect eluent is used, immediately stop the patient infusion, evaluate the patient’s radiation absorbed dose, and monitor for the effects of radiation to critical organs such as bone marrow . Permanently discontinue use of the affected CardioGen-82 generator [see Dosage and Administration ( 2.5 )] . 5.2 Excess Radiation Exposure with Failure to Follow the Eluate Testing Protocol Excess radiation exposure occurs when the Sr 82 and Sr 85 levels in the Rubidium Chloride Rb 82 Injection exceed the specified generator eluate limits. Strictly adhere to the eluate testing protocol to minimize radiation exposure to the patient. Stop using the CardioGen-82 generator when the expiration limits are reached [see Dosage and Administration ( 2.6 , 2.7 , 2.8 )]. 5.3 Risks Associated with Pharmacologic Stress Pharmacologic induction of cardiovascular stress may be associated with serious adverse reactions such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction, and cerebrovascular events. Perform pharmacologic stress testing in accordance with the pharmacologic stress agent’s prescribing information and only in the setting where cardiac resuscitation equipment and trained staff are readily available. 5.4 Cumulative Radiation Exposure: Long-Term Risk of Cancer Rubidium chloride Rb 82 contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Use the lowest dose of Rubidium Chloride Rb 82 Injection necessary for imaging and ensure safe handling to protect the patient and health care providers . Encourage patients to void as soon as a study is completed and as often as possible thereafter for a least one hour [see Dosage and Administration ( 2.1 , 2.2 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: High Level Radiation Exposure with Use of Incorrect Eluent [see Warnings and Precautions ( 5.1 )] Excess Radiation Exposure with Failure to Follow Eluate Testing Protocol [see Warnings and Precautions ( 5.2 )] The following serious adverse reactions have been identified during post-approval use of CardioGen-82. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Radiation Exposure High level radiation exposure to the bone marrow from using an incorrect eluent. Excess radiation exposure due to insufficient eluate testing. To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc. at 1-800-257-8151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

8.1 Pregnancy Risk Summary There are no data available on the use of rubidium chloride Rb 82 in pregnant women. Animal reproductive studies have not been conducted with rubidium chloride Rb 82. However, all radiopharmaceuticals, including Rubidium Chloride Rb 82 Injection generated by CardioGen-82, have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering Rubidium Chloride Rb 82 Injection administration to a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from rubidium-82 (Rb 82) and the gestational timing of exposure. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.