NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term studies have been performed to evaluate carcinogenic potential, mutagenicity potential, or to determine whether rubidium chloride Rb 82 may affect fertility in males or females.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

CardioGen-82NDC: 0270-0091-01Rubidium Rb 82 Generator Cardiogen Generator Container Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of CardioGen-82, used to produce Rubidium Chloride Rb 82 Injection, in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In human studies, myocardial activity was noted within the first minute after peripheral intravenous injection of rubidium chloride Rb 82. When areas of infarction or ischemia are present in the myocardium, they are visualized within minutes to minutes after injection as photon-deficient, or cold, areas on the myocardial scan. In patients with reduced cardiac function, transit of the injected dose from the peripheral infusion site to the myocardium may be delayed [see Dosage and Administration (2.3)]. Blood flow brings Rb 82 to all areas of the body during the first pass of circulation. Accordingly, visible uptake is also observed in other highly vascularized organs, such as the kidneys, liver, spleen, and lungs.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. With physical half-life of 75 seconds, Rb 82 is converted by radioactive decay into stable Kr 82 gas, which is passively expired by the lungs.

ADVERSE REACTIONS SECTION.

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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Radiation ExposureHigh level radiation exposure to the bone marrow from using an incorrect eluent.Excess radiation exposure due to insufficient eluate testing.. 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)] 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.

BOXED WARNING SECTION.

WARNING: HIGH LEVEL RADIATION EXPOSURE WITH USE OF INCORRECT ELUENT and FAILURE TO FOLLOW THE ELUATE TESTING PROTOCOL. High Level Radiation Exposure with Use of Incorrect Eluent Patients are exposed to high radiation levels when the CardioGen-82 generator is eluted with the incorrect eluent due to high strontium (Sr) 82 and Sr 85 breakthrough levels. Use only additive-free 0.9% Sodium Chloride Injection to elute the generator.If an incorrect solution is used to elute the CardioGen-82 generator: Immediately stop the patient infusion;Evaluate the patients radiation absorbed dose, and monitor for the effects of radiation to critical organs such as bone marrow;Permanently discontinue the use of the affected generator [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)]. Excess Radiation Exposure with Failure to Follow the Eluate Testing ProtocolExcess radiation exposure occurs when the levels of Sr 82 or Sr 85 in the Rubidium Chloride Rb 82 Injection exceed specified limits.Strictly adhere to the generator eluate testing protocol, to minimize the risk of excess radiation exposure, including daily testing and additional testing at Alert Limits.Stop using the generator if it reaches any of its Expiration Limits:17 for the generators cumulative eluate volume60 days post generator calibration dateAn eluate Sr 82 level of 0.01 microCi /mCi Rb 82An eluate Sr 85 level of 0.1 microCi /mCi Rb 82 [see Dosage and Administration (2.5, 2.6, 2.7, 2.8) and Warnings and Precautions (5.2)] Use only additive-free 0.9% Sodium Chloride Injection to elute the generator.. If an incorrect solution is used to elute the CardioGen-82 generator: Immediately stop the patient infusion;Evaluate the patients radiation absorbed dose, and monitor for the effects of radiation to critical organs such as bone marrow;Permanently discontinue the use of the affected generator [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)]. Immediately stop the patient infusion;. Evaluate the patients radiation absorbed dose, and monitor for the effects of radiation to critical organs such as bone marrow;. Permanently discontinue the use of the affected generator [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)]. Strictly adhere to the generator eluate testing protocol, to minimize the risk of excess radiation exposure, including daily testing and additional testing at Alert Limits.. Stop using the generator if it reaches any of its Expiration Limits:17 for the generators cumulative eluate volume60 days post generator calibration dateAn eluate Sr 82 level of 0.01 microCi /mCi Rb 82An eluate Sr 85 level of 0.1 microCi /mCi Rb 82 [see Dosage and Administration (2.5, 2.6, 2.7, 2.8) and Warnings and Precautions (5.2)] 17 for the generators cumulative eluate volume. 60 days post generator 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 [see Dosage and Administration (2.5, 2.6, 2.7, 2.8) and Warnings and Precautions (5.2)] WARNING: HIGH LEVEL RADIATION EXPOSURE WITH USE OF INCORRECT ELUENT and FAILURE TO FOLLOW THE ELUATE TESTING PROTOCOLSee full prescribing information for complete boxed warning.High Level Radiation Exposure with Use of Incorrect Eluent Using the incorrect eluent can cause high Strontium (Sr) 82 and Sr 85 breakthrough levels. Use only additive-free 0.9% Sodium Chloride Injection to elute CardioGen-82. If an incorrect solution is used to elute CardioGen-82: Immediately stop the patient infusion;Evaluate the patients radiation absorbed dose and monitor for the effects of radiation to critical organs such as bone marrow;Permanently discontinue use of the affected generator. (2.5, 2.9, 5.1)Excess Radiation Exposure with Failure to Follow the Eluate Testing ProtocolExcess radiation exposure occurs when the levels of Sr 82 or Sr 85 in the Rubidium Chloride Rb 82 Injection exceed limits. Strictly adhere to the generator eluate testing protocol. Stop using the generator if it reaches any of its Expiration Limits. (2.5, 2.6, 2.7, 5.2). Use only additive-free 0.9% Sodium Chloride Injection to elute CardioGen-82. If an incorrect solution is used to elute CardioGen-82: Immediately stop the patient infusion;Evaluate the patients radiation absorbed dose and monitor for the effects of radiation to critical organs such as bone marrow;Permanently discontinue use of the affected generator. (2.5, 2.9, 5.1). Immediately stop the patient infusion;. Evaluate the patients radiation absorbed dose and monitor for the effects of radiation to critical organs such as bone marrow;. Permanently discontinue use of the affected generator. (2.5, 2.9, 5.1). Strictly adhere to the generator eluate testing protocol. Stop using the generator if it reaches any of its Expiration Limits. (2.5, 2.6, 2.7, 5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term studies have been performed to evaluate carcinogenic potential, mutagenicity potential, or to determine whether rubidium chloride Rb 82 may affect fertility in males or females.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Rb 82 is analogous to potassium ion (K+) in its biochemical behavior and is extracted by the myocardium in proportion to the blood flow. Rb+ participates in the sodium-potassium (Na+/K+) ion exchange pumps that are present in cell membranes. The intracellular uptake of Rb 82 requires maintenance of ionic gradient across cell membranes. Rb 82 radioactivity is increased in viable myocardium reflecting intracellular retention, while the tracer is cleared from necrotic or infarcted tissue.. 12.2 Pharmacodynamics. In human studies, myocardial activity was noted within the first minute after peripheral intravenous injection of rubidium chloride Rb 82. When areas of infarction or ischemia are present in the myocardium, they are visualized within minutes to minutes after injection as photon-deficient, or cold, areas on the myocardial scan. In patients with reduced cardiac function, transit of the injected dose from the peripheral infusion site to the myocardium may be delayed [see Dosage and Administration (2.3)]. Blood flow brings Rb 82 to all areas of the body during the first pass of circulation. Accordingly, visible uptake is also observed in other highly vascularized organs, such as the kidneys, liver, spleen, and lungs.. 12.3 Pharmacokinetics. With physical half-life of 75 seconds, Rb 82 is converted by radioactive decay into stable Kr 82 gas, which is passively expired by the lungs.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. In descriptive, prospective, blinded image interpretation study of adult patients with known or suspected coronary artery disease, myocardial perfusion deficits in stress and rest PET images obtained with ammonia 13 (n 111) or rubidium chloride Rb 82 (n 82) were compared to changes in stenosis flow reserve (SFR) as determined by coronary angiography. PET perfusion defects at rest and stress for seven cardiac regions (anterior, apical, anteroseptal, posterolateral, anterolateral, posterolateral, and inferior walls) were graded on scale of (normal) to (severe). Values for stenosis flow reserve, defined as flow at maximum coronary vasodilatation relative to rest flow, ranged from (total occlusion) to (normal). With increasing impairment of flow reserve, the subjective PET defect severity increased. PET defect score of or higher was positively correlated with flow reserve impairment (SFR<3).A systematic review of published literature was conducted using pre-defined inclusion/exclusion criteria which resulted in identification of 10 studies evaluating the use of Rb 82 PET myocardial perfusion imaging (MPI) for the identification of coronary artery disease as defined by catheter-based angiography. In these studies, the patient was the unit of analysis and 50% stenosis was the threshold for clinically significant coronary artery disease (CAD). Of these 10 studies, studies were included in meta-analysis for sensitivity (excluding one study with 100% sensitivity) and studies were included in meta-analysis of specificity (excluding studies with 100% specificity). random effects model yielded overall estimates of sensitivity and specificity of 92% (95% CI: 89% to 95%) and 81% (95% CI: 76% to 86%), respectively. The use of meta-analysis in establishing performance characteristics is limited, particularly by the possibility of publication bias (positive results being more likely to be published than negative results) which is difficult to detect especially when based on limited number of small studies.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. 11.1 Generator Characteristics. CardioGen-82 (rubidium Rb 82 generator) contains accelerator-produced Sr 82 adsorbed on stannic oxide in lead-shielded column and provides means to produce sterile nonpyrogenic Rubidium Chloride Rb 82 Injection, radioactive diagnostic agent, for intravenous use. The chemical form of Rb 82 is 82RbCl.The amount (mCi) of Rb 82 obtained in each elution will depend on the potency of the generator. When eluted at rate of 50 mL/minute, each generator eluate at the end of elution should not contain more than 0.02 microCi of Sr 82 and not more than 0.2 microCi of Sr 85 per mCi of Rubidium Chloride Rb 82 Injection, and not more than mcg of tin per mL of eluate.. 11.2 Nuclear Physical Characteristics. Rb 82 decays by positron emission and associated gamma emission with physical half-life of 75 seconds. Table shows the annihilation photons released following positron emission which are useful for detection and imaging studies.The decay modes of Rb 82 are: 95.5% by positron emission, resulting in the production of annihilation radiation, i.e., two 511 keV gamma rays; and 4.5% by electron capture, resulting in the emission of prompt gamma rays of predominantly 776.5 keV. Both decay modes lead directly to the formation of stable krypton 82 (Kr 82).Table 3. Principal Radiation Emission Data for Rb 82RadiationMean PercentPer DisintegrationMean Energy(keV)Annihilation photons (2)191.01511 (each)Gamma rays13-15776.5The specific gamma ray constant for Rb 82 is 6.1 R/hour-mCi at cm. The first half-value layer is 0.7 cm of lead (Pb). Table shows range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of lead. For example, the use of 7.0 cm thickness of Pb will attenuate the radiation emitted by factor of about 1,000.Table 4. Radiation Attenuation by Lead ShieldingShield Thickness (Pb) cmAttenuation Factor0.7 0.5 2.3 10-1 4.7 10-2 7.0 10-3 9.3 10-4 Sr 82 (half-life of 25 days) decays to Rb 82. To correct for physical decay of Sr 82, Table shows the fractions that remain at selected intervals after the time of calibration.Table 5. Physical Decay Chart: Sr 82 half-life 25 days Days Fraction Remaining Days Fraction Remaining Days Fraction Remaining 0Calibration time 21 0.55941 0.32110.973 22 0.543420.31220.946 230.529430.30430.920 24 0.514440.29540.895 250.500450.28750.871 26 0.486460.27960.847 27 0.473470.27270.824 28 0.460480.26480.801 29 0.448490.25790.779 30 0.435500.250100.758 310.423510.243110.737 320.412520.237120.717 330.401530.230130.697 340.390540.224140.678 350.379550.218150.660360.369560.212160.642370.359570.206170.624380.349580.200180.607390.339590.195190.591400.330600.189200.574 To correct for physical decay of Rb 82, Table shows the fraction of Rb 82 remaining in all 15 second intervals up to 300 seconds after time of calibration.Table 6. Physical Decay Chart: Rb 82 half-life 75 seconds Seconds Fraction Remaining Seconds Fraction Remaining 0Elution time 11650.218150.8711800.19300.7581950.165450.662100.144600.5742250.125750.52400.109900.4352550.0951050.3792700.0831200.332850.0721350.2873000.0631500.25.

DOSAGE & ADMINISTRATION SECTION.

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 procedure via intravenous infusion at 50 mL/minute or 20 mL/minute. (2.2)Do not exceed maximum dose of 2,220 MBq (60 mCi) or maximum volume of 100 mL per rest or stress component of 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 longer circulation time is anticipated, wait for 120 seconds. Image acquisition is 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). 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 procedure via intravenous infusion at 50 mL/minute or 20 mL/minute. (2.2). Do not exceed maximum dose of 2,220 MBq (60 mCi) or maximum volume of 100 mL per rest or stress component of 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 longer circulation time is anticipated, wait for 120 seconds. Image acquisition is 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. DosingThe recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of 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 catheter inserted into large peripheral vein.Do not exceed maximum dose of 2,220 MBq (60 mCi) or maximum volume of 100 mL per rest or stress component of procedure.Administration InstructionsObserve 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 study is completed and as often as possible thereafter for at least one hour [see Warnings and Precautions (5.4)].. 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 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 ImagingAdminister 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 minutes.Stress ImagingBegin the study at least 10 minutes after completion of the resting dose infusion, to allow for sufficient Rb 82 decay. Administer 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 minutes.Rest and Stress ImagingIf longer circulation time is anticipated (e.g., in 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.. Administer 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 minutes.. Begin the study at least 10 minutes after completion of the resting dose infusion, to allow for sufficient Rb 82 decay. Administer 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 minutes.. If longer circulation time is anticipated (e.g., in 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 Operators Manual for the setup and administration of Rubidium Chloride Rb 82 Injection.. 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%. 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 Operators 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. 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 for the estimated maximum available Rb 82 activity as function of generator age for generator with an initial 100 mCi of Sr 82 [see Dosage and Administration (2.8)]. 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. maximum of 12 hours from the initial port closure penetration is permitted, after which the bag must be replaced for the next patient. 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. 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 for the estimated maximum available Rb 82 activity as function of generator age for 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 PrecautionsUse 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 Operators Manual for performing all eluate testing as described.Mandatory Eluate TestingPerform 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 total elution volume has passed through the generator column, orSr 82 level reaches 0.002 microCi per mCi Rb 82, orSr 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 days 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 CalibrationBefore 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 new generatorAfter installation of new CardioGen-82 Accessory Package, Item 001710Every 14 daysCalibration ProcedureSet 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 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 through 4). Repeat steps through for flow rate of 20 mL/min.Daily Quality Control ProcedureEach 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 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 generators 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. 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 Operators Manual for performing all eluate testing as described.. Daily Before administering Rubidium Chloride Rb 82 Injection to the first patient each day.. Repeat as indicated after an Alert Limit has been detected.. 14 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.. After installation of new generator. After installation of new CardioGen-82 Accessory Package, Item 001710. Every 14 days. Set 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 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 through 4). 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 through 4).. Repeat steps through for flow rate of 20 mL/min.. 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 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 generators 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. The infusion system will elute the generator with 50 mL of additive-free 0.9% Sodium Chloride Injection at 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 generators 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. 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 has passed through the generator column60 days post calibration dateAn eluate Sr 82 level of 0.01 microCi/mCi Rb 82An eluate Sr 85 level of 0.1 microCi/mCi Rb 82. total elution volume of 17 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 provides an estimate of the maximum available activity of Rb 82 as function of generator age for generator with an initial 100 mCi of Sr 82.Table 1. Maximum Available Rb 82 Activity Based on Generator Age1 Generator Age (days)2 Maximum Rb 82 Activity per Elution0 to 1760 mCi (2,220 MBq)2450 mCi (1,850 MBq)3240 mCi (1,480 MBq)4230 mCi (1,110 MBq)5720 mCi (740 MBq)6019 mCi (703 MBq)1Estimate is based on 100 mCi (3,700 MBq) Sr 82 generator at calibration.2Generator age at which delivery limit is reached varies with generator activity at release. For example, 90 mCi (3,330 MBq) generator and 150 mCi (5,550 MBq) generator will reach 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 AdultsOrgana,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 Adrenals7.5610.65.03Bone Osteogenic cells Bone Surface1.86-------107---9.81Brain0.68.292.96Breast0.827.031.72Gall Bladder Wall3.178.472.82Heart Wall16.58.182.67Kidneys20.049.182.5Liver4.28.102.5Lower Large Intestine Wall2.8451.85.14Lungsd 10.78.252.84Muscles1.298.142.66Ovaries1.4110.24.29Pancreas8.859.13.46Red Marrow1.19919.84Skin1.147.031.75Small Intestine4.769.624.03Spleen6.618.12.54Stomach8.147.842.26Testes0.827.251.7Thymus1.497.842.33Thyroid6.118.072.57Upper Large Intestine5.9423.73.62Urinary Bladder Wall1.6121.92.9Uterus3.729.143.32Total Body1.77Not calculatedNot calculatedEffective Dosee 4.74f 23.44.03a 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 10-13 Sv/Bq.d Calculated from ICRP 66e Calculated from ICRP 60f Stress phase only.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Rubidium Rb 82 generator used to produce Rubidium Chloride Rb 82 Injection: strontium-82 (Sr 82), with an activity of 3,330 MBq to 5,550 MBq (90 mCi to 150 mCi) at calibration time, adsorbed on hydrous stannic oxide column.. Rubidium Rb 82 generator used to produce Rubidium Chloride Rb 82 Injection: 3,330 MBq to 5,550 MBq (90 mCi to 150 mCi) of strontium-82 (Sr 82) at calibration time, adsorbed on hydrous stannic oxide column. (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. In elderly patients with clinically important decrease in cardiac function, lengthen the delay between infusion and image acquisition [see Dosage and Administration (2.3)]. Observe for the possibility of fluid overload.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedCardioGen-82 (rubidium Rb 82 generator), used to produce Rubidium Chloride Rb 82 Injection, is supplied in lead shield surrounded by labeled plastic container with an activity at calibration time of 3,330 MBq to 5,550 MBq (90 mCi to 150 mCi) of Sr 82 adsorbed on hydrous stannic oxide column (NDC 0270-0091-01). The container label provides complete assay data for each generator.Storage and HandlingStore the generator at 20C to 25C (68F to 77F) [See USP Controlled Room Temperature].Receipt, transfer, possession, storage, disposal or use of this product is subject to the radioactive material regulations and licensing requirements of the U.S. Nuclear Regulatory Commission (NRC), Agreement States or Licensing States as appropriate. Do not dispose of the generator in regular refuse systems.For questions about the disposal of the CardioGen-82 generator, contact Bracco Diagnostics Inc. at 1-800-447-6883, option 3.

INDICATIONS & USAGE SECTION.

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 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Post-Study VoidingInstruct patients to void after completion of each image acquisition session and as often as possible for one hour after completion of the PET scan [see Warnings and Precautions (5.4)].PregnancyAdvise pregnant woman of the potential risk to fetus [see Use in Specific Populations (8.1)].LactationAdvise lactating women that exposure to Rb 82 through breast milk can be minimized if breastfeeding is discontinued when Rubidium Chloride Rb 82 Injection is administered. Advise lactating women not to resume breastfeeding for at least one hour after administration of Rubidium Chloride Rb 82 Injection [see Use in Specific Populations (8.2)].Manufactured forBracco Diagnostics Inc.Princeton, NJ 08540Manufactured By GE Healthcare, Medi-Physics, Inc.Arlington Heights, IL 60004CardioGen-82(R) Rubidium 82 Generators, Infusion Systems, and Accessories contain proprietary technology covered by one or more patents listed at www.braccoimaging.com/us-en/patents.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Rb 82 is analogous to potassium ion (K+) in its biochemical behavior and is extracted by the myocardium in proportion to the blood flow. Rb+ participates in the sodium-potassium (Na+/K+) ion exchange pumps that are present in cell membranes. The intracellular uptake of Rb 82 requires maintenance of ionic gradient across cell membranes. Rb 82 radioactivity is increased in viable myocardium reflecting intracellular retention, while the tracer is cleared from necrotic or infarcted tissue.

PREGNANCY SECTION.

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 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.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration,5/2026 Dosing Using the Infusion System Model 510 (2.2)-Removed Eluate Testing Protocol for Infusion System Model 510 (2.6)-Removed Expiration Limits of CardioGen-82 (2.7).

SPL UNCLASSIFIED SECTION.

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.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Lactation: Do not resume breastfeeding until at least one hour after administration of Rubidium Chloride Rb 82 Injection. (8.2). 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 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.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of rubidium chloride Rb 82 in human milk, the effects on the breastfed infant or the effects on milk production. Due to the short half-life of Rb 82 (75 seconds), exposure of breastfed infant through breast milk can be minimized by temporary discontinuation of breastfeeding (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Rubidium Chloride Rb 82 Injection, any potential adverse effects on the breastfed child from Rb 82 or from the underlying maternal condition. Clinical ConsiderationsExposure to Rb 82 through breast milk can be minimized if breastfeeding is discontinued when Rubidium Chloride Rb 82 Injection is administered. Do not resume breastfeeding until at least one hour after administration of Rubidium Chloride Rb 82 Injection.. 8.4 Pediatric Use. The safety and effectiveness of CardioGen-82, used to produce Rubidium Chloride Rb 82 Injection, in pediatric patients have not been established.. 8.5 Geriatric Use. In elderly patients with clinically important decrease in cardiac function, lengthen the delay between infusion and image acquisition [see Dosage and Administration (2.3)]. Observe for the possibility of fluid overload.

WARNINGS AND PRECAUTIONS SECTION.

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 generators 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 patients 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 agents 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 patients 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 study is completed and as often as possible thereafter for least one hour [see Dosage and Administration (2.1, 2.2)].