DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Use only additive free 0.9% Sodium Chloride InjectionUSP to elute the generator. (2.5)Use CardioGen-82 only with the CardioGen-82 Infusion SystemModel 510 or Model 1700. (2.4) The recommended adult (70 kg) single dose of rubidium Rb82 chloride injection is 1,480 MBq (40 mCi), with range of 1,110MBq to 2,220 MBq (30 mCi to 60 mCi). Do not exceed single dose of 2,220 MBq (60 mCi) per rest or stress component of procedure. (2.2) Administer via intravenous infusion at rate of 50 mL/minute(Model 510 and Model 1700), or at rate of 20 mL/minute (Model1700 only). (2.2) Use the lowest dose necessary to obtain adequate cardiacvisualization. Individualize the dose depending on multiple factors,including patient weight, imaging equipment and acquisition type usedto perform the procedure. (2.2) Start imaging acquisition 60 to 90 seconds after completionof the infusion; if longer circulation time is anticipated, waitfor 120 seconds. Image acquisition is typically minutes long. (2.3) To obtain both rest and stress images, wait 10 minutes aftercompletion of the rest image acquisition, then administer the pharmacologicstress agent in accordance with its prescribing information. Then,at time interval after the administration of the pharmacologic stressagent that is in accordance with its prescribing information, infusethe second dose of rubidium Rb 82 chloride and complete the stressimage acquisition. (2.3) Use only additive free 0.9% Sodium Chloride InjectionUSP to elute the generator. (2.5). Use CardioGen-82 only with the CardioGen-82 Infusion SystemModel 510 or Model 1700. (2.4) The recommended adult (70 kg) single dose of rubidium Rb82 chloride injection is 1,480 MBq (40 mCi), with range of 1,110MBq to 2,220 MBq (30 mCi to 60 mCi). Do not exceed single dose of 2,220 MBq (60 mCi) per rest or stress component of procedure. (2.2) Administer via intravenous infusion at rate of 50 mL/minute(Model 510 and Model 1700), or at rate of 20 mL/minute (Model1700 only). (2.2) Use the lowest dose necessary to obtain adequate cardiacvisualization. Individualize the dose depending on multiple factors,including patient weight, imaging equipment and acquisition type usedto perform the procedure. (2.2) Start imaging acquisition 60 to 90 seconds after completionof the infusion; if longer circulation time is anticipated, waitfor 120 seconds. Image acquisition is typically minutes long. (2.3) To obtain both rest and stress images, wait 10 minutes aftercompletion of the rest image acquisition, then administer the pharmacologicstress agent in accordance with its prescribing information. Then,at time interval after the administration of the pharmacologic stressagent that is in accordance with its prescribing information, infusethe second dose of rubidium Rb 82 chloride and complete the stressimage acquisition. (2.3) 2.1 Radiation Safety Drug Handling. Rubidium Rb 82 is radioactive drug and should be handledwith appropriate safety measures to minimize radiation exposure duringadministration [See Warnings and Precautions (5.5)]. Use only additive-free 0.9% Sodium Chloride InjectionUSP to elute the generator[see BoxedWarning, Contraindications (4), and Warnings and Precautions (5.1)].Limit the use of radiopharmaceuticals to physicians whoare qualified by training and experience in the safe use and handlingof radionuclides and whose experience and training have been approvedby the appropriate government agency authorized to license the useof radionuclides.Wear waterproof gloves and effective shielding when handlingrubidium Rb 82 chloride injection and the infusion system.Observe aseptic techniques in all drug handling.Visually inspect the drug for particulate matter and discolorationprior to administration whenever solution and container permit. Donot administer eluate from the generator if there is any evidenceof foreign matter.. Use only additive-free 0.9% Sodium Chloride InjectionUSP to elute the generator[see BoxedWarning, Contraindications (4), and Warnings and Precautions (5.1)].. Limit the use of radiopharmaceuticals to physicians whoare qualified by training and experience in the safe use and handlingof radionuclides and whose experience and training have been approvedby the appropriate government agency authorized to license the useof radionuclides.. Wear waterproof gloves and effective shielding when handlingrubidium Rb 82 chloride injection and the infusion system.. Observe aseptic techniques in all drug handling.. Visually inspect the drug for particulate matter and discolorationprior to administration whenever solution and container permit. Donot administer eluate from the generator if there is any evidenceof foreign matter.. 2.2 Rubidium Rb 82 Chloride Injection Dosage. The recommended adult single dose of rubidiumRb 82 chloride injection per rest or stress component of PET myocardialperfusion imaging (MPI) procedure is 1,480 MBq (40 mCi) with rangeof 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi).Do not exceed single dose of 2,220 MBq (60 mCi).Use the lowest dose necessary, consistent with the goalof as low as reasonably achievable (ALARA), to obtain adequate cardiacvisualization. The choice of dosage and infusion rate should be madeat the discretion of the physician performing the Rb 82 PET myocardialperfusion imaging scan, based on his/her consideration of multiplefactors, including patient body mass, and the imaging equipment andacquisition methodology used to perform the procedure. For example,3D image acquisition may require doses at the lower end of the recommendedrange, compared to 2D imaging.Administer the single dose at 50 mL/minute, or at20 mL/minute (CardioGen-82 Infusion System Model 1700 only), through catheter inserted into large peripheral vein; do notto exceed total infusion volume of 100 mL.Instruct patients to void as soon as study is completedand as often as possible thereafter for at least one hour.The maximum available activity (delivery limit) will decreaseas the generator ages [see Dosage and Administration (2.9)]. Do not exceed single dose of 2,220 MBq (60 mCi).. Use the lowest dose necessary, consistent with the goalof as low as reasonably achievable (ALARA), to obtain adequate cardiacvisualization. The choice of dosage and infusion rate should be madeat the discretion of the physician performing the Rb 82 PET myocardialperfusion imaging scan, based on his/her consideration of multiplefactors, including patient body mass, and the imaging equipment andacquisition methodology used to perform the procedure. For example,3D image acquisition may require doses at the lower end of the recommendedrange, compared to 2D imaging.. Administer the single dose at 50 mL/minute, or at20 mL/minute (CardioGen-82 Infusion System Model 1700 only), through catheter inserted into large peripheral vein; do notto exceed total infusion volume of 100 mL.. Instruct patients to void as soon as study is completedand as often as possible thereafter for at least one hour.. The maximum available activity (delivery limit) will decreaseas the generator ages [see Dosage and Administration (2.9)]. 2.3 Image Acquisition Guidelines. Administer two separate single doses tocomplete rest and stress myocardial perfusion imaging as follows:For Rest Imaging:Administer single (rest) rubidium Rb 82 chloride dose;Start imaging 60 to 90 seconds after completion of the infusionof the rest dose, and acquire images for minutes.For StressImaging:Begin the study 10 minutes after completion of the restingdose infusion, to allow for sufficient Rb 82 decay;Administer pharmacologic stress agent in accordance withits prescribing information;After the administration of the pharmacologic stress agent,administer the second dose of Rb 82 at the time interval accordingto the prescribing information of the pharmacologic stress agent;Start imaging 60 to 90 seconds after completion of the stressRb 82 chloride dose infusion, and acquire images for minutes.For BothRest and Stress Imaging:If longer circulation time is anticipated (e.g., in apatient with severe left ventricular dysfunction), start imaging 120seconds after the rest dose.Acquisition may be started immediately post-injection ifdynamic imaging is needed.. Administer single (rest) rubidium Rb 82 chloride dose;. Start imaging 60 to 90 seconds after completion of the infusionof the rest dose, and acquire images for minutes.. Begin the study 10 minutes after completion of the restingdose infusion, to allow for sufficient Rb 82 decay;. Administer pharmacologic stress agent in accordance withits prescribing information;. After the administration of the pharmacologic stress agent,administer the second dose of Rb 82 at the time interval accordingto the prescribing information of the pharmacologic stress agent;. Start imaging 60 to 90 seconds after completion of the stressRb 82 chloride dose infusion, and acquire images for minutes.. If longer circulation time is anticipated (e.g., in apatient with severe left ventricular dysfunction), start imaging 120seconds after the rest dose.. Acquisition may be started immediately post-injection ifdynamic imaging is needed.. 2.4 Infusion System. Use CardioGen-82 only with the CardioGen-82 Infusion SystemModel 510 or the CardioGen-82 Infusion System Model 1700, which arespecifically designed for use with the generator and capable of accuratemeasurement and delivery of doses of rubidium Rb 82 chloride injection.If using the CardioGen-82 Infusion System Model 510, referto the Eluate Testing Protocol in Section 2.6 [see Dosageand Administration (2.6)].If using the CardioGen-82 Infusion System Model 1700, referto the Eluate Testing Protocol in Section 2.7 [see Dosageand Administration (2.7)]. Follow instructions in the CardioGen-82 Infusion SystemModel 510 or Model 1700 Operators Manual for the set up and intravenousinfusion of rubidium Rb 82 chloride injection dose(s).1,2 The generator, when used with either infusion system, provides+- 10% accuracy for rubidium Rb 82 chloride injection between dosesof 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi).. Use CardioGen-82 only with the CardioGen-82 Infusion SystemModel 510 or the CardioGen-82 Infusion System Model 1700, which arespecifically designed for use with the generator and capable of accuratemeasurement and delivery of doses of rubidium Rb 82 chloride injection.If using the CardioGen-82 Infusion System Model 510, referto the Eluate Testing Protocol in Section 2.6 [see Dosageand Administration (2.6)].If using the CardioGen-82 Infusion System Model 1700, referto the Eluate Testing Protocol in Section 2.7 [see Dosageand Administration (2.7)]. If using the CardioGen-82 Infusion System Model 510, referto the Eluate Testing Protocol in Section 2.6 [see Dosageand Administration (2.6)].. If using the CardioGen-82 Infusion System Model 1700, referto the Eluate Testing Protocol in Section 2.7 [see Dosageand Administration (2.7)].. Follow instructions in the CardioGen-82 Infusion SystemModel 510 or Model 1700 Operators Manual for the set up and intravenousinfusion of rubidium Rb 82 chloride injection dose(s).1,2 The generator, when used with either infusion system, provides+- 10% accuracy for rubidium Rb 82 chloride injection between dosesof 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi).. 2.5 Directions for Eluting Rubidium Rb 82 Chloride Injection. Use only additive-free 0.9 SodiumChloride Injection USP to elute the generator[see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].Prepare the 0.9 Sodium Chloride InjectionUSP for use with the Saline TagPrepare the intravenous port in accordance with the DOSAGEAND ADMINISTRATION section of the approved prescribing informationof the 0.9 Sodium Chloride Injection USP.The intravenous administration port of the sodium chloridecontainer must be penetrated only one time.Strap the saline tag provided with the CardioGen-82 InfusionSystem on the additive-free 0.9% Sodium Chloride Injection USP containerand install on the CardioGen-82 Infusion System.Once the container port closure is penetrated, it shouldremain installed on the CardioGen-82 Infusion System for its entireperiod of use. maximum of 12 hours from the initial port closurepenetration is permitted, after which the bag must be replaced forthe next patient.Allow at least 10 minutes between elutionsfor regeneration of Rb 82.If the CardioGen-82 Infusion System Model510 is used, discard the first 50 mL eluate each day the generatoris eluted, and employ proper safety precautions since the eluate containsradioactivity. If the CardioGen-82 Infusion System Model 1700 isused, the system will automatically discard the first 50 mL of eluateeach day the generator is eluted.If the CardioGen-82 Infusion System Model510 is used, maintain an on-going record of all eluate volumes (washing,testing, dosing volumes), including summary of the cumulative volumeof eluate from the generator. If the CardioGen-82 Infusion SystemModel 1700 is used, the system software automatically records andsaves all eluate volumes (all flushing, Quality Control (QC) testing,and patient infusions), representing the cumulative volume of eluateeach day the generator is eluted.. Use only additive-free 0.9 SodiumChloride Injection USP to elute the generator[see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].. Prepare the 0.9 Sodium Chloride InjectionUSP for use with the Saline TagPrepare the intravenous port in accordance with the DOSAGEAND ADMINISTRATION section of the approved prescribing informationof the 0.9 Sodium Chloride Injection USP.The intravenous administration port of the sodium chloridecontainer must be penetrated only one time.Strap the saline tag provided with the CardioGen-82 InfusionSystem on the additive-free 0.9% Sodium Chloride Injection USP containerand install on the CardioGen-82 Infusion System.Once the container port closure is penetrated, it shouldremain installed on the CardioGen-82 Infusion System for its entireperiod of use. maximum of 12 hours from the initial port closurepenetration is permitted, after which the bag must be replaced forthe next patient.. Prepare the intravenous port in accordance with the DOSAGEAND ADMINISTRATION section of the approved prescribing informationof the 0.9 Sodium Chloride Injection USP.. The intravenous administration port of the sodium chloridecontainer must be penetrated only one time.. Strap the saline tag provided with the CardioGen-82 InfusionSystem on the additive-free 0.9% Sodium Chloride Injection USP containerand install on the CardioGen-82 Infusion System.. Once the container port closure is penetrated, it shouldremain installed on the CardioGen-82 Infusion System for its entireperiod of use. maximum of 12 hours from the initial port closurepenetration is permitted, after which the bag must be replaced forthe next patient.. Allow at least 10 minutes between elutionsfor regeneration of Rb 82.. If the CardioGen-82 Infusion System Model510 is used, discard the first 50 mL eluate each day the generatoris eluted, and employ proper safety precautions since the eluate containsradioactivity. If the CardioGen-82 Infusion System Model 1700 isused, the system will automatically discard the first 50 mL of eluateeach day the generator is eluted.. If the CardioGen-82 Infusion System Model510 is used, maintain an on-going record of all eluate volumes (washing,testing, dosing volumes), including summary of the cumulative volumeof eluate from the generator. If the CardioGen-82 Infusion SystemModel 1700 is used, the system software automatically records andsaves all eluate volumes (all flushing, Quality Control (QC) testing,and patient infusions), representing the cumulative volume of eluateeach day the generator is eluted.. 2.6 CardioGen-82 InfusionSystem Model 510 Eluate Testing Protocol. Use only additive-free 0.9% Sodium Chloride InjectionUSP for all elutions [see Boxed Warning, Contraindications (4), and Warningsand Precautions (5.1)].Observe aseptic techniquethroughout.Follow all instructions in the CardioGen-82 Infusion SystemModel 510 Operators Manual for performing all eluate testing as described.Before administeringrubidium Rb 82 chloride injection to the first patient each day, performthe following testing:Strontium Alert Limits and MandatoryEluate Testing:Use an ionization chamber-type dose calibrator for eluatetesting.Daily, before administering rubidium Rb 82 chloride injectionto any patient, perform an eluate testing to determine Rb 82, Sr 82,and Sr 85 levelsPerform additional daily eluate tests after detecting anyof the following Alert Limits:14 total elution volume has passed through the generatorcolumn, orSr 82 level reaches 0.002 uCi per mCi Rb 82, orSr 85 level reaches 0.02 uCi per mCi Rb 82. Perform the additional daily eluate tests at time points determinedby the days elution volume; tests are performed every 750 mL.For example, if an Alert Limit were reached and the clinicalsite eluted less than 750 mL from the generator during the day, thenno additional eluate tests would have been performed that day.If the same clinical site the next day eluted 1,500 mL fromthe generator, then the site would have performed three tests thatday: 1) the required daily test that precedes any patient dosing,2) test at the 750 mL elution point, and 3) test at the 1,500mL elution points.If generators Alert Limit is reached, the clinical siteperforms the additional daily tests (at intervals of 750 mL) eachsubsequent day the generator is used. The additional tests are necessaryto promptly detect excessive Sr 82 and/or Sr 85 in eluates. Rubidium EluateLevel Testing:Set dose calibrator for Rb 82 as recommended by the manufactureror use the Co-60 setting and divide the reading obtained by 0.548.Obtain the reading from the instrument in millicuries.Elute the generator with 50 mL of Sodium Chloride InjectionUSP and discard the eluate (first elution).Allow at least 10 minutes for the regeneration of Rb 82,then elute the generator with 50 mL of Sodium Chloride Injection USPat rate of 50 mL/min and collect the eluate in stoppered glassvial (plastic containers are not suitable). Note the exact time ofend of elution (E.O.E.).Using the dose calibrator, determine the activity of Rb82 and note the time of the reading. Correct the reading for decayto the E.O.E. using the appropriate decay factor for Rb 82 (see Table1). Note: If the reading is taken 1/2 minutes after end of elution,multiply the dose calibrator reading by to correct for decay. Strontium Eluate Level Testing: Using the sample obtained for the Rb 82 activity determination,allow the sample to stand for at least one hour to allow for the completedecay of Rb 82.Measure the activity of the sample in dose calibratorat the setting recommended by the manufacturer for Rb 82 and/or Sr82. As an alternative, use the Co-60 setting and the reading obtaineddivided by 0.548. Set the instrument to read in microcuriesand record in the display. Calculate the ratio (R) of Sr 85/Sr 82 on the day (postcalibration)of the measurement using the ratio of Sr 85/Sr 82 on the day of calibrationprovided on the generator label and the Sr 85/Sr 82 Ratio Factor fromTable 2. Determine using the following equation:R =[Sr 85] [Sr 82] on calibration date Ratio Factor on the day (post-calibration)of measurement Use correction factor (F) of 0.478 to compensate for thecontribution of Sr 85 to the reading.Calculate the amount of Sr 82 in the sample using the followingequation:Sr 82 (uCi) dose calibration reading (uCi)/ [1 (R) (F)] Example: dose calibrator reading (uCi)= 0.8; Sr85/Sr82 ratio (R) 1.48; correction factor (F) 0.478.Sr 82 (uCi) 0.8 [1 (1.48)(0.478)] 0.47Determine if Sr 82 in the eluate exceeds an Alert or ExpirationLimit by dividing the uCi of Sr 82 by the mCi of Rb 82 at End of Elution(see below for further instructions based on the Sr 82 level)Example: 0.47 uCi or Sr 82; 50 mCi of Rb 82 E.O.E.0.47uCi Sr 82 50 mCi Rb 82 0.0094 uCi/mCi Rb 82 (is above Alert Limitof 0.002; additional daily eluate testing must be performed) Determine if Sr 85 in the eluate exceeds an Alert or ExpirationLimit by multiplying the result obtained in step 10 by (R) as calculatedin step (above).Example: 0.0094 1.48 0.014 uCi Sr85/mCi Rb 82 (test result is below Alert and Expiration Limits)Use Table to calculatethe decay factor for Rb 82; step (above).Elution timeTABLE1Physical Decay Chart: Rb 82 half-life 75 secondsSeconds FractionRemaining Seconds FractionRemaining 1.000 165 0.218 150.8711800.190300.7581950.165450.6602100.144600.5742250.125750.5002400.109900.4352550.0951050.3792700.0831200.3302850.0721350.2873000.063150 0.250 Use Table to calculatethe ratio (R) of Sr 85/Sr 82; step (above).Day of calibrationTABLE2Sr 85/Sr 82 Ratio Chart (Sr 85 1/2 65 days, Sr 82 1/2 25 days)DaysRatio FactorDaysRatio FactorDaysRatio Factor01.00151.29301.6711.02161.31311.7021.03171.34321.7331.05181.36331.7641.07191.38341.7951.09201.41351.8261.11211.43361.8571.13221.46371.8881.15231.48381.9191.17241.51391.95101.19251.53401.98111.21261.56412.01121.23271.58422.05131.25281.61141.27291.64. Use an ionization chamber-type dose calibrator for eluatetesting.. Daily, before administering rubidium Rb 82 chloride injectionto any patient, perform an eluate testing to determine Rb 82, Sr 82,and Sr 85 levels. Perform additional daily eluate tests after detecting anyof the following Alert Limits:14 total elution volume has passed through the generatorcolumn, orSr 82 level reaches 0.002 uCi per mCi Rb 82, orSr 85 level reaches 0.02 uCi per mCi Rb 82. Perform the additional daily eluate tests at time points determinedby the days elution volume; tests are performed every 750 mL.For example, if an Alert Limit were reached and the clinicalsite eluted less than 750 mL from the generator during the day, thenno additional eluate tests would have been performed that day.If the same clinical site the next day eluted 1,500 mL fromthe generator, then the site would have performed three tests thatday: 1) the required daily test that precedes any patient dosing,2) test at the 750 mL elution point, and 3) test at the 1,500mL elution points.If generators Alert Limit is reached, the clinical siteperforms the additional daily tests (at intervals of 750 mL) eachsubsequent day the generator is used. The additional tests are necessaryto promptly detect excessive Sr 82 and/or Sr 85 in eluates. 14 total elution volume has passed through the generatorcolumn, or. Sr 82 level reaches 0.002 uCi per mCi Rb 82, or. Sr 85 level reaches 0.02 uCi per mCi Rb 82. Perform the additional daily eluate tests at time points determinedby the days elution volume; tests are performed every 750 mL.. For example, if an Alert Limit were reached and the clinicalsite eluted less than 750 mL from the generator during the day, thenno additional eluate tests would have been performed that day.. If the same clinical site the next day eluted 1,500 mL fromthe generator, then the site would have performed three tests thatday: 1) the required daily test that precedes any patient dosing,2) test at the 750 mL elution point, and 3) test at the 1,500mL elution points.. If generators Alert Limit is reached, the clinical siteperforms the additional daily tests (at intervals of 750 mL) eachsubsequent day the generator is used. The additional tests are necessaryto promptly detect excessive Sr 82 and/or Sr 85 in eluates.. Set dose calibrator for Rb 82 as recommended by the manufactureror use the Co-60 setting and divide the reading obtained by 0.548.Obtain the reading from the instrument in millicuries.. Elute the generator with 50 mL of Sodium Chloride InjectionUSP and discard the eluate (first elution).. Allow at least 10 minutes for the regeneration of Rb 82,then elute the generator with 50 mL of Sodium Chloride Injection USPat rate of 50 mL/min and collect the eluate in stoppered glassvial (plastic containers are not suitable). Note the exact time ofend of elution (E.O.E.).. Using the dose calibrator, determine the activity of Rb82 and note the time of the reading. Correct the reading for decayto the E.O.E. using the appropriate decay factor for Rb 82 (see Table1). Note: If the reading is taken 1/2 minutes after end of elution,multiply the dose calibrator reading by to correct for decay. Strontium Eluate Level Testing: Using the sample obtained for the Rb 82 activity determination,allow the sample to stand for at least one hour to allow for the completedecay of Rb 82.. Measure the activity of the sample in dose calibratorat the setting recommended by the manufacturer for Rb 82 and/or Sr82. As an alternative, use the Co-60 setting and the reading obtaineddivided by 0.548. Set the instrument to read in microcuriesand record in the display. Calculate the ratio (R) of Sr 85/Sr 82 on the day (postcalibration)of the measurement using the ratio of Sr 85/Sr 82 on the day of calibrationprovided on the generator label and the Sr 85/Sr 82 Ratio Factor fromTable 2. Determine using the following equation:R =[Sr 85] [Sr 82] on calibration date Ratio Factor on the day (post-calibration)of measurement Use correction factor (F) of 0.478 to compensate for thecontribution of Sr 85 to the reading.. Calculate the amount of Sr 82 in the sample using the followingequation:Sr 82 (uCi) dose calibration reading (uCi)/ [1 (R) (F)] Example: dose calibrator reading (uCi)= 0.8; Sr85/Sr82 ratio (R) 1.48; correction factor (F) 0.478.Sr 82 (uCi) 0.8 [1 (1.48)(0.478)] 0.47. Determine if Sr 82 in the eluate exceeds an Alert or ExpirationLimit by dividing the uCi of Sr 82 by the mCi of Rb 82 at End of Elution(see below for further instructions based on the Sr 82 level)Example: 0.47 uCi or Sr 82; 50 mCi of Rb 82 E.O.E.0.47uCi Sr 82 50 mCi Rb 82 0.0094 uCi/mCi Rb 82 (is above Alert Limitof 0.002; additional daily eluate testing must be performed) Determine if Sr 85 in the eluate exceeds an Alert or ExpirationLimit by multiplying the result obtained in step 10 by (R) as calculatedin step (above).Example: 0.0094 1.48 0.014 uCi Sr85/mCi Rb 82 (test result is below Alert and Expiration Limits). 2.7 CardioGen-82 InfusionSystem Model 1700 Eluate Testing Protocol. Use only additive-free0.9% Sodium Chloride Injection USP for all elutions[see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].Observe aseptictechnique throughout.Follow all instructionsin the CardioGen-82 Infusion System Model 1700 Operators Manual forperforming all elute testing as described.PerformMandatory Eluate Testing to determine Rb 82, Sr 82, and Sr 85 levels:Daily Before administering rubidiumRb 82 chloride injection to the first patient each day.Repeat as indicated after an Alert Limithas been detected. Alert Limits: 14 total elution volume has passed through the generatorcolumn, orSr 82 level reaches 0.002 uCi per mCi Rb 82, orSr 85 level reaches 0.02 uCi per mCi Rb 82.The CardioGen-82 Infusion System Model1700 will automatically indicate when alert limits have been reached,and will require that additional tests be performed, to facilitatethe prompt detection of excessive levels of Sr 82 and/or Sr 85 shouldthey occur.These additional daily eluate tests willbe performed at intervals determined by the days elution volume,and will be enforced by the System software. Specifically, the infusionsystem will require the user to perform additional eluate testingafter each 750 mL of elution volume when any Alert Limit parameterhas been reached.Infusion System Calibration: Before administering rubidiumRb 82 chloride injection to the first patient:After installation of new generator and or installation of anew CardioGen-82 Accessory Package, Item 001710, perform the RubidiumRb 82 Chloride Injection Dose Calibration (performed using an externaldose calibrator).Set dose calibrator for Rb 82 as recommendedby the manufacturer. Obtain the reading from the instrument in millicuries.Following the prompts in the GraphicalUser Interface (GUI) for the CardioGen-82 Infusion System Model 1700,elute the generator with additive-free 0.9% Sodium Chloride InjectionUSP at rate of 50 mL/min and collect the eluate in the stopperedvial specifically provided for use with the CardioGen-82 InfusionSystem Model 1700 (alternative vials, glass or plastic are not suitable).Note the exact time of end of elution (EOE).Using the external dose calibrator, assaythe eluate at exactly 2:30, 3:45, or 5:00 minutes after EOE.Following the prompts in the GUI forthe CardioGen-82 Infusion System Model 1700, enter the Rb 82 readingfrom the dose calibrator and the time since EOE.The infusion system software will automaticallycalculate the Calibration Ratio.If the ratio is within +/- 2% (0.98 to 1.02), the infusionsystem will allow acceptance of the calibration factor that was usedfor the elution.If the ratio is not within +/- 2% (0.98 to 1.02), the systemrequires another calibration elution (steps through 4).Repeat steps through for flow rateof 20 mL/min.Performadditional system calibration every 14 days.Daily Quality Control: Eluate (Strontium Level) Testingand Dose ConstancyEach day, before administeringrubidium Rb 82 chloride injection, perform the following test, includingMandatory Eluate Testing:Daily QualityControl (performed on-board the CardioGen-82 InfusionSystem Model 1700, using the gamma (Sr) detector):Place the stoppered vial, which is specifically provided for use with the CardioGen-82 Infusion System, Model 1700(alternative vials, glass or plastic are not suitable) in the Sr detectorwell on the CardioGen-82 Infusion System Model 1700 and, followingthe prompts in the GUI for the infusion system, initiate the DailyQuality Control workflow.The infusion system will automaticallyperform the Sr Detector Background Reading.The infusion system will automaticallyperform the Generator Column Wash.Strontium Level Test and Dose Constancy:The infusion system will elute the generator with 50 mLof additive-free 0.9% Sodium Chloride Injection USP at rate of 50mL/min into the stoppered vial (which is specifically provided foruse with the CardioGen-82 Infusion System Model 1700).The Sr detector measures the Rb 82 and strontium in the50 mL elution.The infusion system software will automatically calculatethe Sr 82 and Sr 85 levels on the day (post calibration) of the measurementusing the ratio of Sr 85/Sr 82 on the day of calibration providedon the generator label, and using the full exponential decay calculationfor each, accounting for the generators age.Using the Rb 82 and strontium measurements, the infusionsystem software will automatically calculate uCi Sr 82/mCi Rb 82 anduCi Sr 85/mCi Rb 82. The GUI will automatically indicate if the resultsexceed Alert or Expiration Limits.The infusion system software will automatically calculateDose Constancy.Constancy Check of the Sr detector: Theinfusion system GUI will prompt the user to perform the constancycheck of the Sr detector.Place the external constancy source in the detector wellof the infusion system.The infusion system software will automatically calculatethe constancy of the Sr detector versus the external constancy sourcewhen instructed.. Daily Before administering rubidiumRb 82 chloride injection to the first patient each day.. Repeat as indicated after an Alert Limithas been detected. Alert Limits: 14 total elution volume has passed through the generatorcolumn, orSr 82 level reaches 0.002 uCi per mCi Rb 82, orSr 85 level reaches 0.02 uCi per mCi Rb 82.. 14 total elution volume has passed through the generatorcolumn, or. Sr 82 level reaches 0.002 uCi per mCi Rb 82, or. Sr 85 level reaches 0.02 uCi per mCi Rb 82.. The CardioGen-82 Infusion System Model1700 will automatically indicate when alert limits have been reached,and will require that additional tests be performed, to facilitatethe prompt detection of excessive levels of Sr 82 and/or Sr 85 shouldthey occur.. These additional daily eluate tests willbe performed at intervals determined by the days elution volume,and will be enforced by the System software. Specifically, the infusionsystem will require the user to perform additional eluate testingafter each 750 mL of elution volume when any Alert Limit parameterhas been reached.. Set dose calibrator for Rb 82 as recommendedby the manufacturer. Obtain the reading from the instrument in millicuries.. Following the prompts in the GraphicalUser Interface (GUI) for the CardioGen-82 Infusion System Model 1700,elute the generator with additive-free 0.9% Sodium Chloride InjectionUSP at rate of 50 mL/min and collect the eluate in the stopperedvial specifically provided for use with the CardioGen-82 InfusionSystem Model 1700 (alternative vials, glass or plastic are not suitable).Note the exact time of end of elution (EOE).. Using the external dose calibrator, assaythe eluate at exactly 2:30, 3:45, or 5:00 minutes after EOE.. Following the prompts in the GUI forthe CardioGen-82 Infusion System Model 1700, enter the Rb 82 readingfrom the dose calibrator and the time since EOE.. The infusion system software will automaticallycalculate the Calibration Ratio.If the ratio is within +/- 2% (0.98 to 1.02), the infusionsystem will allow acceptance of the calibration factor that was usedfor the elution.If the ratio is not within +/- 2% (0.98 to 1.02), the systemrequires another calibration elution (steps through 4).. If the ratio is within +/- 2% (0.98 to 1.02), the infusionsystem will allow acceptance of the calibration factor that was usedfor the elution.. If the ratio is not within +/- 2% (0.98 to 1.02), the systemrequires another calibration elution (steps through 4).. Repeat steps through for flow rateof 20 mL/min.. Place the stoppered vial, which is specifically provided for use with the CardioGen-82 Infusion System, Model 1700(alternative vials, glass or plastic are not suitable) in the Sr detectorwell on the CardioGen-82 Infusion System Model 1700 and, followingthe prompts in the GUI for the infusion system, initiate the DailyQuality Control workflow.. The infusion system will automaticallyperform the Sr Detector Background Reading.. The infusion system will automaticallyperform the Generator Column Wash.. Strontium Level Test and Dose Constancy:The infusion system will elute the generator with 50 mLof additive-free 0.9% Sodium Chloride Injection USP at rate of 50mL/min into the stoppered vial (which is specifically provided foruse with the CardioGen-82 Infusion System Model 1700).The Sr detector measures the Rb 82 and strontium in the50 mL elution.The infusion system software will automatically calculatethe Sr 82 and Sr 85 levels on the day (post calibration) of the measurementusing the ratio of Sr 85/Sr 82 on the day of calibration providedon the generator label, and using the full exponential decay calculationfor each, accounting for the generators age.Using the Rb 82 and strontium measurements, the infusionsystem software will automatically calculate uCi Sr 82/mCi Rb 82 anduCi Sr 85/mCi Rb 82. The GUI will automatically indicate if the resultsexceed Alert or Expiration Limits.The infusion system software will automatically calculateDose Constancy.. The infusion system will elute the generator with 50 mLof additive-free 0.9% Sodium Chloride Injection USP at rate of 50mL/min into the stoppered vial (which is specifically provided foruse with the CardioGen-82 Infusion System Model 1700).. The Sr detector measures the Rb 82 and strontium in the50 mL elution.. The infusion system software will automatically calculatethe Sr 82 and Sr 85 levels on the day (post calibration) of the measurementusing the ratio of Sr 85/Sr 82 on the day of calibration providedon the generator label, and using the full exponential decay calculationfor each, accounting for the generators age.. Using the Rb 82 and strontium measurements, the infusionsystem software will automatically calculate uCi Sr 82/mCi Rb 82 anduCi Sr 85/mCi Rb 82. The GUI will automatically indicate if the resultsexceed Alert or Expiration Limits.. The infusion system software will automatically calculateDose Constancy.. Constancy Check of the Sr detector: Theinfusion system GUI will prompt the user to perform the constancycheck of the Sr detector.Place the external constancy source in the detector wellof the infusion system.The infusion system software will automatically calculatethe constancy of the Sr detector versus the external constancy sourcewhen instructed.. Place the external constancy source in the detector wellof the infusion system.. The infusion system software will automatically calculatethe constancy of the Sr detector versus the external constancy sourcewhen instructed.. 2.8 CardioGen-82 Expiration. If using the CardioGen-82 Infusion SystemModel 510, stop use of the CardioGen-82 generator once any one ofthe following Expiration Limits is reached. If using the CardioGen-82Infusion System Model 1700, the software will automatically indicate,and will stop use of, the CardioGen-82 generator once any one of thefollowing Expiration Limits is reached.A total elution volume of 17 has passed through the generatorcolumn, or42 days post calibration date, orAn eluate Sr 82 level of 0.01 uCi /mCi Rb 82, orAn eluate Sr 85 level of 0.1 uCi /mCi Rb 82.. total elution volume of 17 has passed through the generatorcolumn, or. 42 days post calibration date, or. An eluate Sr 82 level of 0.01 uCi /mCi Rb 82, or. An eluate Sr 85 level of 0.1 uCi /mCi Rb 82.. 2.9 CardioGen-82 Dose Delivery Limit. The maximum availableactivity (delivery limit) will decrease as the generator ages. Certaindoses, including the maximum recommended dose [60 mCi 2,220 MBq)]are not achievable for the entire shelf-life of the generator. Table3 provides an estimate of the maximum available activity of RubidiumRb 82 (Delivery Limit) as function of generator age.1Estimateis based on 100 mCi (3,700 MBq) Sr 82 generator at calibration.2Generator age at which delivery limitis reached varies with generator activity at release. For example,a 90 mCi (3,330 MBq) generator and 150 mCi (5,550 MBq) generatorwill reach delivery limit <60 mCi at >= 14 days and >= 33 days,respectively.Table Rubidium Rb 82 Dose Delivery Limit Based on GeneratorAge1 Generator Age (days)2 Maximum Rubidium Dose (Delivery Limit)0-1760 mCi (2,220 MBq)2450 mCi (1,850 MBq)3240 mCi (1,480 MBq)4230 mCi (1,110 MBq). 2.10 Radiation Dosimetry. The estimated absorbed radiation dosesfor Rb 82, Sr 82, and Sr 85 from an intravenous injection of rubidiumRb 82 chloride are shown in Table 4.aRb 82 doses are averagesof rest and stress dosimetry data (see Senthamizhchelvan et al.1,2). To calculate organ doses (mrem) from Rb 82, multiplythe dose coefficient for each organ by the administered activity inmCi.bSr 82 and Sr 85 dosesare 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 strontiumin uCi.3 cTo convert to SI units, insert the dose coefficient into the formulain parentheses, e.g. for adrenals 7.56 mrem/mCi 7.56 uSv/37 MBq= 2.04 10-13 Sv/Bq. dCalculated from ICRP 66 eCalculated from ICRP 60 fStressphase only Table Adult Absorbed RadiationDose CoefficientOrgana,b Rb 82(Average for Rest and Stress)mrem/mCi (uSv/3.7 MBq)c Sr 82mrem/uCi(uSv/3.7kBq)c Sr 85mrem/uCi(uSv/3.7kBq)c Adrenals7.56 10.6 5.03 Bone Osteogenic cells 1.86 --- ---Bone Surface---- 1079.81Brain0.60 8.292.96 Breast0.82 7.03 1.72 Gall Bladder Wall3.17 8.47 2.82 Heart Wall 16.5 8.18 2.67 Kidneys 20.04 9.18 2.50 Liver 4.20 8.10 2.50 Lower Large Intestine Wall2.84 51.8 5.14 Lungsd 10.78.25 2.84 Muscles 1.29 8.14 2.66 Ovaries 1.41 10.2 4.29 Pancreas 8.85 9.10 3.46 Red Marrow 1.19 91.0 9.84 Skin1.14 7.03 1.75 Small Intestine 4.76 9.62 4.03 Spleen6.61 8.10 2.54 Stomach8.14 7.84 2.26 Testes0.82 7.25 1.70 Thymus1.49 7.84 2.33 Thyroid6.118.07 2.57 Upper Large Intestine5.9423.7 3.62 Urinary Bladder Wall1.6121.9 2.90 Uterus 3.729.14 3.32 Total Body 1.77Not calculated Not calculated Effective Dosee 4.74f 23.44.03.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. RubidiumRb 82 chloride injection safety and effectiveness in pediatric patientshave not been established.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. To report SUSPECTED ADVERSE REACTIONS, contactBracco Diagnostics Inc at 1-800-257-5181 or FDA at 1-800-FDA-1088or www.fda.gov/medwatch (6). 6.1 Post marketing Experience. The following serious adverse reactions havebeen identified during postapproval use of CardioGen-82. Because thesereactions are reported voluntarily from population of uncertainsize, it is not always possible to reliably estimate their frequencyor establish causal relationship to drug exposure.Radiation ExposureHigh level radiation exposure to the bone marrow hasoccurred in some patients due to Sr 82 and Sr 85 breakthrough in theeluate when an incorrect solution was used to elute the rubidium Rb82 generator [see Boxed Warning andWarnings and Precautions (5.1)].Excess radiationexposure has occurred in some patients who received rubidium Rb 82chloride injections at clinical sites where generator eluate testingappeared insufficient [see Boxed Warning, Warnings and Precautions (5.2),and Dosage and Administration (2.6 or 2.7)].

BOXED WARNING SECTION.

WARNING: HIGH LEVEL RADIATION EXPOSURE WITH USE OF INCORRECT ELUENTAND FAILURE TO FOLLOW THE ELUATE TESTING PROTOCOL. High LevelRadiation Exposure with Use of Incorrect EluentPatients are exposed to high radiation levels when the CardioGen-82generator is eluted with the incorrect eluent due to high Sr 82 andSr 85 breakthrough levels [see Warnings and Precautions (5.1)]Use only additive-free 0.9% Sodium Chloride InjectionUSP to elute the generator [see Dosage and Administration (2.5)] Immediately stop the patient infusion and permanentlydiscontinue the use of the affected CardioGen-82 generator if theincorrect solution is used to elute the generator [see Contraindications (4)] Evaluate the patients radiation absorbed dose andmonitor for the effects of radiation to critical organs such as bonemarrow [see Dosage and Administration (2.10)] ExcessRadiation Exposure with Failure to Follow the Eluate Testing ProtocolExcess radiation exposure occurs when the levels of Sr82 or Sr 85 in the rubidium Rb 82 chloride injection exceed specifiedlimits [see Warnings and Precautions (5.2)]Record each generator eluate volume, including wasteand test volumes, and keep record of the cumulative eluate volume [see Dosage and Administration (2.5)] Strictly adhere to the generator eluate testing protocol,to minimize the risk of excess radiation exposure, including dailytesting and additional testing at Alert Limits [see Dosageand Administration (2.6, 2.7)] Stop using the generator if it reaches any of itsExpiration Limits:17 for the generators cumulative eluate volume,or42 days post generator calibration date, orAn eluate Sr 82 level of 0.01 uCi /mCi Rb 82, orAn eluate Sr 85 level of 0.1 uCi /mCi Rb 82 [see Dosage and Administration (2.8)] Use only additive-free 0.9% Sodium Chloride InjectionUSP to elute the generator [see Dosage and Administration (2.5)] Immediately stop the patient infusion and permanentlydiscontinue the use of the affected CardioGen-82 generator if theincorrect solution is used to elute the generator [see Contraindications (4)] Evaluate the patients radiation absorbed dose andmonitor for the effects of radiation to critical organs such as bonemarrow [see Dosage and Administration (2.10)] Record each generator eluate volume, including wasteand test volumes, and keep record of the cumulative eluate volume [see Dosage and Administration (2.5)] Strictly adhere to the generator eluate testing protocol,to minimize the risk of excess radiation exposure, including dailytesting and additional testing at Alert Limits [see Dosageand Administration (2.6, 2.7)] Stop using the generator if it reaches any of itsExpiration Limits:17 for the generators cumulative eluate volume,or42 days post generator calibration date, orAn eluate Sr 82 level of 0.01 uCi /mCi Rb 82, orAn eluate Sr 85 level of 0.1 uCi /mCi Rb 82 [see Dosage and Administration (2.8)] 17 for the generators cumulative eluate volume,or. 42 days post generator calibration date, or. An eluate Sr 82 level of 0.01 uCi /mCi Rb 82, or. An eluate Sr 85 level of 0.1 uCi /mCi Rb 82 [see Dosage and Administration (2.8)] WARNING: HIGH LEVEL RADIATION EXPOSURE WITHUSE OF INCORRECT ELUENT AND FAILURE TO FOLLOW THE ELUATE TESTING PROTOCOLPlease see fullprescribing information for complete boxed warningHigh Level RadiationExposure with Use of Incorrect EluentUsing the incorrect eluent can cause high Strontium (Sr) 82and Sr 85 breakthrough levels (5.1) Use only additive-free 0.9% Sodium Chloride InjectionUSP to elute the generator (2.5) Immediately stop the patient infusion and permanentlydiscontinue the use of the affected CardioGen-82 generator if theincorrect solution is used to elute the generator (4) Evaluate the patients radiation absorbed dose andmonitor for the effects of radiation to critical organs such as bonemarrow (2.10) Excess RadiationExposure with Failure to Follow the Eluate Testing ProtocolExcess radiation exposure occurs when thelevels of Sr 82 or Sr 85 in the rubidium Rb 82 chloride injectionexceed limits (5.2) Record eluate volume, including waste and test volumes (2.5) Strictly adhere to the generator eluate testing protocol (2.6, 2.7) Stop using the generator if it reaches any of itsExpiration Limits (2.8) Use only additive-free 0.9% Sodium Chloride InjectionUSP to elute the generator (2.5) Immediately stop the patient infusion and permanentlydiscontinue the use of the affected CardioGen-82 generator if theincorrect solution is used to elute the generator (4) Evaluate the patients radiation absorbed dose andmonitor for the effects of radiation to critical organs such as bonemarrow (2.10) Record eluate volume, including waste and test volumes (2.5) Strictly adhere to the generator eluate testing protocol (2.6, 2.7) Stop using the generator if it reaches any of itsExpiration Limits (2.8).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term studies have been performed to evaluatecarcinogenic potential, mutagenicity potential, or to determine whetherrubidium Rb 82 chloride injection may affect fertility in males orfemales.

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 rapidly extracted by the myocardiumproportional to the blood flow. Rb+ participatesin the sodium-potassium (Na+/K+) ion exchange pumps that are present in cell membranes.The intracellular uptake of Rb 82 requires maintenance of ionic gradientacross cell membranes. Rb 82 radioactivity is increased in viablemyocardium reflecting intracellular retention, while the tracer iscleared rapidly from necrotic or infarcted tissue.. 12.2 Pharmacodynamics. Inhuman studies, myocardial activity was noted within the first minuteafter peripheral intravenous injection of Rb 82. When areas of infarctionor ischemia are present in the myocardium, they are visualized within2-7 minutes after injection as photon-deficient, or cold, areason the myocardial scan. In patients with reduced cardiac function,transit of the injected dose from the peripheral infusion site tothe myocardium may be delayed [see Dosage and Administration (2.3)]. Blood flow brings Rb 82 to all areas ofthe body during the first pass of circulation. Accordingly, visibleuptake is also observed in other highly vascularized organs, suchas the kidneys, liver, spleen and lungs.. 12.3 Pharmacokinetics. Witha physical half-life of 75 seconds, Rb 82 is very rapidly convertedby radioactive decay into trace amount of stable Kr-82 gas, whichis passively expired by the lungs.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. In adescriptive, prospective, blinded image interpretation study6 of adult patients with known or suspected coronaryartery disease, myocardial perfusion deficits in stress and rest PETimages obtained with ammonia 13 (n 111) or rubidium Rb 82 chloride(n 82) were compared to changes in stenosis flow reserve (SFR) asdetermined by coronary angiography. PET perfusion defects at restand stress for seven cardiac regions (anterior, apical, anteroseptal,posterolateral, anterolateral, posterolateral, and inferior walls)were graded on scale of (normal) to (severe). Values for stenosisflow reserve, defined as flow at maximum coronary vasodilatation relativeto rest flow, ranged from (total occlusion) to (normal). Withincreasing impairment of flow reserve, the subjective PET defect severityincreased. PET defect score of or higher was positively correlatedwith flow reserve impairment (SFR<3).A system review of published literature was conducted using pre-definedinclusion/exclusion criteria which resulted in identification of 10studies evaluating the use of Rb 82 PET myocardial perfusion imaging(MPI) for the identification of coronary artery disease as definedby catheter-based angiography. In these studies, the patient was theunit of analysis and 50% stenosis was the threshold for clinicallysignificant coronary artery disease (CAD). Of these 10 studies, 9studies were included in meta-analysis for sensitivity (excludingone study with 100% sensitivity) and studies were included in ameta-analysis of specificity (excluding studies with 100% specificity).A random effects model yielded overall estimates of sensitivity andspecificity of 92% (95% CI: 89% to 95%) and 81% (95% CI: 76% to 86%),respectively. The use of meta-analysis in establishing performancecharacteristics is limited, particularly by the possibility of publicationbias (positive results being more likely to be published than negativeresults) which is difficult to detect especially when based on limitednumber of small studies.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS CardioGen-82is contraindicated if solution other than additive free 0.9% SodiumChloride Injection USP has been used to elute the generator at anytime. Immediately stop the patient infusion and permanently discontinuethe use of the affected CardioGen-82 generator whenever the incorrecteluent is used [see Boxed Warning,Contraindications (4), and Warningsand Precautions (5.1)] CardioGen-82 is contraindicated if solutionother than additive free 0.9 Sodium Chloride Injection USP has beenused to elute the generator at any time. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. 11.1 Chemical Characteristics. CardioGen-82 contains accelerator-produced Sr82 adsorbed on stannic oxide in lead-shielded column and providesa means for obtaining sterile nonpyrogenic solutions of rubidium Rb82 chloride injection. The chemical form of Rb 82 is 82RbCl.The amount (millicuries)of Rb 82 obtained in each elution will depend on the potency of thegenerator. When eluted at rate of 50 mL/minute, each generator eluateat the end of elution should not contain more than 0.02 microcurieof Sr 82 and not more than 0.2 microcurie of Sr 85 per millicurieof rubidium Rb 82 chloride injection, and not more than microgramof tin per mL of eluate.. 11.2 Physical Characteristics. Rb 82 decays by positron emission and associatedgamma emission with physical half-life of 75 seconds.4 Table shows the annihilation photons releasedfollowing positron emission which are useful for detection and imagingstudies.The decay modes of Rb 82 are:95.5% by positron emission, resulting in the production of annihilationradiation, i.e., two 511 keV gamma rays; and 4.5% by electron capture,resulting in the emission of prompt gamma rays of predominantly776.5 keV. Both decay modes lead directly to the formation of stableKr-82.4 TABLE5Principal Radiation Emission DataMean PercentMean EnergyRadiationPer Disintegration(keV)Annihilation photons (2)191.01511 (each)Gamma rays13-15776.5The specific gamma ray constant for Rb82 is 6.1 R/hour-millicurie at centimeter. The first half-valuelayer is 0.7 centimeter of lead (Pb). Table shows range of valuesfor the relative attenuation of the radiation emitted by this radionuclidethat results from interposition of various thicknesses of lead.5 For example, the use of 7.0 centimeter thicknessof Pb will attenuate the radiation emitted by factor of about 1,000.TABLE6Radiation Attenuation by Lead ShieldingShield Thickness(Pb) cmAttenuationFactor 0.70.52.310 -1 4.710-2 7.010-3 9.310-4 Sr 82 (half-life of 25 days (600 hrs.))decays to Rb 82. To correct for physical decay of Sr 82, Table showsthe fractions that remain at selected intervals after the time ofcalibration.Calibration timeTABLE7Physical Decay Chart: Sr 82 half-life 25 daysDaysFractionRemaining Days FractionRemaining DaysFractionRemaining 01.000 15 0.660 300.435 10.973160.642310.42320.946170.624320.41230.920180.607330.40140.895190.591340.39050.871200.574350.37960.847210.559360.36970.824220.543370.35980.801230.529380.34990.779240.514390.339100.758250.500400.330110.737260.486410.321120.717270.473420.312130.697280.460140.678290.448To correct for physical decay of Rb 82,Table shows the fraction of Rb 82 remaining in all 15 second intervalsup to 300 seconds after time of calibration [see Dosage andAdministration (2.6, 2.7)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. CardioGen-82 is closed system used to producerubidium Rb 82 chloride injection for intravenous use. CardioGen-82consists of strontium Sr 82 adsorbed on hydrous stannic oxide columnwith an activity of 3,330 MBq to 5,550 MBq (90 millicuries to 150millicuries) Sr 82 at calibration time.. CardioGen-82 consists of strontium Sr 82 adsorbedon hydrous stannic oxide column with an activity of 3,330 MBq to5,550 MBq (90 millicuries to 150 millicuries) Sr 82 at calibrationtime. (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. In elderlypatients 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 [see Warnings and Precautions (5.4)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied CardioGen-82(R) (rubidium Rb 82 generator), used to produce rubidiumRb 82 chloride injection, consists of Sr 82 adsorbed on hydrousstannic oxide column with an activity of 3,330 MBq to 5,550 MBq (90millicuries to 150 millicuries) Sr 82 at calibration time. leadshield surrounded by labeled plastic container encases the generator.The container label provides complete assay data for each generator.Use CardioGen-82 (rubidium Rb 82 Generator) only with an appropriate,properly calibrated infusion system labeled for use with the generator.. 16.2 Disposal. Store the generator at 20 to 25C (68 to 77F) [See USP].Receipt, transfer, possession, storage, disposal or useof this product is subject to the radioactive material regulationsand licensing requirements of the U.S. Nuclear Regulatory Commission(NRC), Agreement States or Licensing States as appropriate. Do notdispose 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.. Store the generator at 20 to 25C (68 to 77F) [See USP].. Receipt, transfer, possession, storage, disposal or useof this product is subject to the radioactive material regulationsand licensing requirements of the U.S. Nuclear Regulatory Commission(NRC), Agreement States or Licensing States as appropriate. Do notdispose 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-82is closed system used to produce rubidium Rb 82 chloride injectionfor intravenous administration. Rubidium Rb 82 chloride injectionis indicated for Positron Emission Tomography (PET) imaging of themyocardium under rest or pharmacologic stress conditions to evaluateregional myocardial perfusion in adult patients with suspected orexisting coronary artery disease.. CardioGen-82 is closed system used to producerubidium Rb 82 chloride injection for intravenous use. Rubidium Rb82 chloride injection is radioactive diagnostic agent indicatedfor Positron Emission Tomography (PET) imaging of the myocardium underrest or pharmacologic stress conditions to evaluate regional myocardialperfusion in adult patients with suspected or existing coronary arterydisease. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. PregnancyAdvise pregnant woman of thepotential risk to fetus [see Use in Specific Populations (8.1)].LactationAdvise lactating women thatexposure to Rb-82 chloride through breast milk can be minimized ifbreastfeeding is discontinued when Rb 82 chloride injection is administered.Advise lactating women not to resume breastfeeding for at least onehour after completion of rubidium Rb 82 infusion [see Usein Specific Populations (8.2)].Post-StudyVoidingInstruct patients to void after completion of each image acquisitionsession and as often as possible for one hour after completion ofthe PET scan [see Warnings and Precautions (5.5)].Manufactured forBracco DiagnosticsInc.Monroe Twp, NJ 08831By GE HealthcareMedi-Physics,Inc.,South Plainfield, NJ 07080CardioGen-82(R) Rubidium 82 Generators, Infusion Systems, and Accessories containproprietary technology covered by one or more patents listed at www.braccoimaging.com/us-en/patents.43-8200HCardioGen-82NDC:0270-0091-01Rubidium Rb 82 GeneratorRevised: October 2020.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term studies have been performed to evaluatecarcinogenic potential, mutagenicity potential, or to determine whetherrubidium Rb 82 chloride injection may affect fertility in males orfemales.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

CardioGen-82NDC: 0270-0091-01Rubidium Rb 82 Generator. cardiogen-82-container-label.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Inhuman studies, myocardial activity was noted within the first minuteafter peripheral intravenous injection of Rb 82. When areas of infarctionor ischemia are present in the myocardium, they are visualized within2-7 minutes after injection as photon-deficient, or cold, areason the myocardial scan. In patients with reduced cardiac function,transit of the injected dose from the peripheral infusion site tothe myocardium may be delayed [see Dosage and Administration (2.3)]. Blood flow brings Rb 82 to all areas ofthe body during the first pass of circulation. Accordingly, visibleuptake is also observed in other highly vascularized organs, suchas the kidneys, liver, spleen and lungs.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Witha physical half-life of 75 seconds, Rb 82 is very rapidly convertedby radioactive decay into trace amount of stable Kr-82 gas, whichis passively expired by the lungs.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere areno data available on the use of rubidium Rb 82 chloride in pregnantwomen. Animal reproductive studies have not been conducted with rubidiumRb 82 chloride injection. However, all radiopharmaceuticals have thepotential to cause fetal harm depending on the fetal stage of developmentand the magnitude of the radiation dose. If considering rubidium Rb82 chloride injection administration to pregnant woman, inform thepatient about the potential for adverse pregnancy outcomes based onthe radiation dose from rubidium Rb 82 and the gestational timingof exposure.The estimatedbackground risk of major birth defects and miscarriage for the indicatedpopulation is unknown. In the U.S. general population, the estimatedbackground risk of major birth defects and miscarriage in clinicallyrecognized pregnancies is 2-4% and 15-20%, respectively.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration,10/2020Directions for Eluting Rubidium Rb 82 Chloride Injection (2.5) CardioGen-82 Infusion System Model 1700 Eluate Testing Protocol (2.7) CardioGen-82 Dose Delivery Limit (2.9).

REFERENCES SECTION.

15 REFERENCES. Senthamizhchelvan S. et al. Human biodistribution and radiationdosimetry of 82Rb. Nucl Med, 2010; 15:1592-99.Senthamizhchelvan S. et al. Radiation dosimetry of 82Rb in humans under pharmacologic stress. Nucl Med2011; 52:485-91.Eckerman, K. F. et al. Users Guide to the DCAL System,ORNL/TM-2001-190; Oak Ridge National Laboratory, Oak Ridge, TN, August,2006.Lederer, and Shirley, V. Table of Isotopes, 7th Edition.Judge, et al. Applied radiation and isotopes (1987); vol38, no. 3: pp 185-90.Demer, L.L. et al. Assessment of coronary artery diseaseseverity by PET: Comparison with quantitative arteriography in 193patients. Circulation 1989; 79:825-35.. Senthamizhchelvan S. et al. Human biodistribution and radiationdosimetry of 82Rb. Nucl Med, 2010; 15:1592-99.. Senthamizhchelvan S. et al. Radiation dosimetry of 82Rb in humans under pharmacologic stress. Nucl Med2011; 52:485-91.. Eckerman, K. F. et al. Users Guide to the DCAL System,ORNL/TM-2001-190; Oak Ridge National Laboratory, Oak Ridge, TN, August,2006.. Lederer, and Shirley, V. Table of Isotopes, 7th Edition.. Judge, et al. Applied radiation and isotopes (1987); vol38, no. 3: pp 185-90.. Demer, L.L. et al. Assessment of coronary artery diseaseseverity by PET: Comparison with quantitative arteriography in 193patients. Circulation 1989; 79:825-35.

SPL UNCLASSIFIED SECTION.

2.1 Radiation Safety Drug Handling. Rubidium Rb 82 is radioactive drug and should be handledwith appropriate safety measures to minimize radiation exposure duringadministration [See Warnings and Precautions (5.5)]. Use only additive-free 0.9% Sodium Chloride InjectionUSP to elute the generator[see BoxedWarning, Contraindications (4), and Warnings and Precautions (5.1)].Limit the use of radiopharmaceuticals to physicians whoare qualified by training and experience in the safe use and handlingof radionuclides and whose experience and training have been approvedby the appropriate government agency authorized to license the useof radionuclides.Wear waterproof gloves and effective shielding when handlingrubidium Rb 82 chloride injection and the infusion system.Observe aseptic techniques in all drug handling.Visually inspect the drug for particulate matter and discolorationprior to administration whenever solution and container permit. Donot administer eluate from the generator if there is any evidenceof foreign matter.. Use only additive-free 0.9% Sodium Chloride InjectionUSP to elute the generator[see BoxedWarning, Contraindications (4), and Warnings and Precautions (5.1)].. Limit the use of radiopharmaceuticals to physicians whoare qualified by training and experience in the safe use and handlingof radionuclides and whose experience and training have been approvedby the appropriate government agency authorized to license the useof radionuclides.. Wear waterproof gloves and effective shielding when handlingrubidium Rb 82 chloride injection and the infusion system.. Observe aseptic techniques in all drug handling.. Visually inspect the drug for particulate matter and discolorationprior to administration whenever solution and container permit. Donot administer eluate from the generator if there is any evidenceof foreign matter.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Lactation: Do not resume breastfeeding until at least onehour after completion of Cardiogen-82 infusion. (8.2) Lactation: Do not resume breastfeeding until at least onehour after completion of Cardiogen-82 infusion. (8.2) 8.1 Pregnancy. Risk SummaryThere areno data available on the use of rubidium Rb 82 chloride in pregnantwomen. Animal reproductive studies have not been conducted with rubidiumRb 82 chloride injection. However, all radiopharmaceuticals have thepotential to cause fetal harm depending on the fetal stage of developmentand the magnitude of the radiation dose. If considering rubidium Rb82 chloride injection administration to pregnant woman, inform thepatient about the potential for adverse pregnancy outcomes based onthe radiation dose from rubidium Rb 82 and the gestational timingof exposure.The estimatedbackground risk of major birth defects and miscarriage for the indicatedpopulation is unknown. In the U.S. general population, the estimatedbackground risk of major birth defects and miscarriage in clinicallyrecognized pregnancies is 2-4% and 15-20%, respectively.. 8.2 Lactation. Risk SummaryThere is no informationregarding the presence of Rb 82 chloride in human milk, the effectson the breastfed infant or the effects on milk production. Due tothe short half-life of rubidium Rb 82 (75 seconds), exposure of abreastfed infant through breast milk can be minimized by temporarydiscontinuation of breastfeeding [See Clinical Considerations]. The developmental and health benefitsof breastfeeding should be considered along with the mothers clinicalneed for Rb 82 chloride injection, any potential adverse effects onthe breastfed child from Rb 82 or from the underlying maternal condition.Clinical ConsiderationsMinimizingExposureExposure to Rb 82 chloride through breastmilk can be minimized if breastfeeding is discontinued when Rb 82chloride injection is administered. Do not resume breastfeeding untilat least one hour after completion of rubidium Rb 82 chloride injectioninfusion.. 8.4 Pediatric Use. RubidiumRb 82 chloride injection safety and effectiveness in pediatric patientshave not been established.. 8.5 Geriatric Use. In elderlypatients 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 [see Warnings and Precautions (5.4)]. 8.6 Renal Impairment. Reductions in renal function are not anticipatedto alter clearance of rubidium Rb 82 chloride injection because Rb82 decays to stable Kr-82 with half-life of 75 seconds and Kr-82is exhaled through the lungs.. 8.7 Hepatic Impairment. Reductions in hepatic function are not anticipatedto alter clearance of rubidium Rb 82 chloride injection.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Pharmacologic induction of cardiovascular stress: May causeserious adverse reactions such as myocardial infarction, arrhythmia,hypotension, broncho-constriction, and cerebrovascular events. Performtesting only in setting where cardiac resuscitation equipment andtrained staff are readily available. (5.3) Pharmacologic induction of cardiovascular stress: May causeserious adverse reactions such as myocardial infarction, arrhythmia,hypotension, broncho-constriction, and cerebrovascular events. Performtesting only in setting where cardiac resuscitation equipment andtrained staff are readily available. (5.3) 5.1 High Level Radiation Exposure with Use of Incorrect Eluent. Use only additive free0.9% Sodium Chloride Injection USP to elute the generator. Applythe provided saline tag to the additive free 0.9% Sodium ChlorideInjection USP container before use. Additives present in other solutions(particularly calcium ions) expose patients to high levels of radiationby causing the release of large amounts of Sr 82 and Sr 85 into theeluate regardless of the generators age or prior use [Dosageand Administration (2.1, 2.5, and 2.6, 2.7)].Immediately stop the patient infusionand discontinue use of the affected CardioGen-82 generator if theincorrect eluent is used and evaluate the patients radiation absorbeddose and monitor for the effects of radiation to critical organs suchas bone marrow. When solutions containing calcium ions areused to elute the generator, high levels of radioactivity are presentin any subsequent eluate, even with the use of additive free 0.9%Sodium Chloride Injection USP. [see BoxedWarning, Dosage and Administration (2.10) and Contraindications (4)].. 5.2 Excess RadiationExposure with Failure to Follow Eluate Testing Protocol. Excess radiation exposure occurswhen the Sr 82 and Sr 85 levels in rubidium Rb 82 chloride injectionsexceed the specified generator eluate limits.Strictly adhere to the eluate testing protocolto minimize radiation exposure to the patient. Stop using the rubidiumgenerator when the expiration limits are reached [see Dosageand Administration (2.6, 2.7) and (2.8)].. 5.3 Risk Associated withPharmacologic Stress. Pharmacologicinduction of cardiovascular stress may be associated with seriousadverse reactions such as myocardial infarction, arrhythmia, hypotension,bronchoconstriction, and cerebrovascular events. Perform pharmacologicstress testing in accordance with the pharmacologic stress agentsprescribing information and only in the setting where cardiac resuscitationequipment and trained staff are readily available.. 5.4 Volume Overload. Patients with congestive heartfailure or the elderly may experience transitory increase in circulatoryvolume load.. 5.5 Cumulative RadiationExposure: Long-Term Risk of Cancer. Rubidium Rb 82 chloride injection, similarto other radiopharmaceuticals, contributes to patients overalllong-term cumulative radiation exposure. Long-term cumulative radiationexposure is associated with an increased risk of cancer. Use the lowestdose of rubidium Rb 82 chloride injection necessary for imaging andensure safe handling to protect the patient and health care worker [see Dosage and Administration (2.1) and (2.2)]. Encouragepatients to void as soon as study is completed and as often as possiblethereafter for least one hour.