Cardiogen-82

• 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 patient’s 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 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 ]
      .
    • Prepare the 0.9 % Sodium Chloride Injection for use with the Saline Tag
      • Prepare the intravenous port in accordance with the approved prescribing information of the 0.9 % Sodium Chloride Injection.
      • The intravenous administration port of the 0.9% Sodium Chloride Injection container must be penetrated only one time.
      • Strap the saline tag provided with the CardioGen-82 Infusion System on the additive-free 0.9% Sodium Chloride Injection container and install on the CardioGen-82 Infusion System.
      • Once the container port closure is penetrated, it should remain installed on the CardioGen-82 Infusion System for its entire period of use. A maximum of 12 hours from the initial port closure penetration is permitted, after which the bag must be replaced for the next patient.
    • Allow at least 10 minutes between elutions for regeneration of Rb 82.
    • If the CardioGen-82 Infusion System Model 510 is used:
      • Discard the first 50 mL eluate each day the generator is eluted and employ proper safety precautions since the eluate contains radioactivity.
      • Maintain an on-going record of all eluate volumes (washing, testing, dosing volumes), including a summary of the cumulative volume of eluate from the generator.
      • Perform eluate testing according to the Eluate Testing Protocol for Infusion System Model 510
        [see Dosage and Administration ]
        .
    • If the CardioGen-82 Infusion System Model 1700 is used:
      • The system software 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 for Infusions System Model 1700
        [see Dosage and Administration ].
    • Stop using the generator when the expiration limits are reached
      [see Dosage and Administration ].
    • The maximum available activity of Rb 82 (dose delivery limit) will decrease as the generator ages. See Table 3 for the estimated maximum available Rb 82 activity as a function of generator age
      [see Dosage and Administration ].

    and Warnings and Precautions

    5.1 High Level Radiation Exposure with Use of Incorrect Eluent

    Additives present in solutions (particularly calcium ions) used by mistake to elute CardioGen-82 expose patients to high levels of radiation by causing the release of large amounts of Sr 82 and Sr 85 into the eluate regardless of the generator’s age or prior use. When solutions containing calcium ions are used, high levels of radioactivity are present in any subsequent eluate even with the use of additive-free 0.9% Sodium Chloride Injection.

    Use only additive-free 0.9% Sodium Chloride Injection to elute CardioGen-82. If an incorrect eluent is used, immediately stop the patient infusion, evaluate the patient’s radiation absorbed dose, and monitor for the effects of radiation to critical organs such as bone marrow. Permanently discontinue use of the affected CardioGen-82 generator

    [see Dosage and Administration ]

    .

    ].

• Record each generator eluate volume, including waste and test volumes, and keep a record of the cumulative eluate volume.
• 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 L for the generator’s cumulative eluate volume
  • 42 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 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 ]
      .
    • Prepare the 0.9 % Sodium Chloride Injection for use with the Saline Tag
      • Prepare the intravenous port in accordance with the approved prescribing information of the 0.9 % Sodium Chloride Injection.
      • The intravenous administration port of the 0.9% Sodium Chloride Injection container must be penetrated only one time.
      • Strap the saline tag provided with the CardioGen-82 Infusion System on the additive-free 0.9% Sodium Chloride Injection container and install on the CardioGen-82 Infusion System.
      • Once the container port closure is penetrated, it should remain installed on the CardioGen-82 Infusion System for its entire period of use. A maximum of 12 hours from the initial port closure penetration is permitted, after which the bag must be replaced for the next patient.
    • Allow at least 10 minutes between elutions for regeneration of Rb 82.
    • If the CardioGen-82 Infusion System Model 510 is used:
      • Discard the first 50 mL eluate each day the generator is eluted and employ proper safety precautions since the eluate contains radioactivity.
      • Maintain an on-going record of all eluate volumes (washing, testing, dosing volumes), including a summary of the cumulative volume of eluate from the generator.
      • Perform eluate testing according to the Eluate Testing Protocol for Infusion System Model 510
        [see Dosage and Administration ]
        .
    • If the CardioGen-82 Infusion System Model 1700 is used:
      • The system software 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 for Infusions System Model 1700
        [see Dosage and Administration ].
    • Stop using the generator when the expiration limits are reached
      [see Dosage and Administration ].
    • The maximum available activity of Rb 82 (dose delivery limit) will decrease as the generator ages. See Table 3 for the estimated maximum available Rb 82 activity as a function of generator age
      [see Dosage and Administration ].

    ,

    2.6 Eluate Testing Protocol for Infusion System Model 510

    Use only additive-free 0.9% Sodium Chloride Injection for all elutions

    [see Warnings and Precautions ]

    .

    Observe aseptic technique throughout.

    Follow all instructions in the CardioGen-82 Infusion System Model 510 Operator’s Manual for performing all eluate testing as described.

    Before administering Rubidium Chloride Rb 82 Injection to the first patient each day, perform the following testing:

    Strontium Alert Limits and Mandatory Eluate Testing:

    • Use an ionization chamber-type dose calibrator for eluate testing.
    • Daily, before administering Rubidium Chloride Rb 82 Injection to any patient, perform an eluate testing to determine Rb 82, Sr 82, and Sr 85 levels
    • Perform additional daily eluate tests after detecting any of the following Alert Limits:
      • 14 L total elution volume has passed through the generator column, or
      • Sr 82 level reaches 0.002 microCi per mCi Rb 82, or
      • Sr 85 level reaches 0.02 microCi per mCi Rb 82.
    • Perform the additional daily eluate tests at time points determined by the day’s elution volume; tests are performed every 750 mL.
      • For example, if an Alert Limit were reached and the clinical site eluted less than 750 mL from the generator during the day, then no additional eluate tests would have been performed that day.
      • If the same clinical site the next day eluted 1,500 mL from the generator, then the site would have performed three tests that day: 1) the required daily test that precedes any patient dosing, 2) a test at the 750 mL elution point, and 3) a test at the 1,500 mL elution points.
      • If a generator’s Alert Limit is reached, the clinical site performs the additional daily tests (at intervals of 750 mL) each subsequent day the generator is used. The additional tests are necessary to promptly detect excessive Sr 82 and/or Sr 85 in eluates.

    Rubidium Eluate Level Testing:

    • Set a dose calibrator for Rb 82 as recommended by the manufacturer or 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 0.9% Sodium Chloride Injection 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 0.9% Sodium Chloride Injection at a rate of 50 mL/min and collect the eluate in a stoppered glass vial (plastic containers are not suitable). Note the exact time of end of elution (E.O.E.).
    • Using the dose calibrator, determine the activity of Rb 82 and note the time of the reading. Correct the reading for decay to the E.O.E. using the appropriate decay factor for Rb 82 (see Table 1). Note: If the reading is taken 2 ½ minutes after end of elution, multiply the dose calibrator reading by 4 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 complete decay of Rb 82.
    • Measure the activity of the sample in a dose calibrator at the setting recommended by the manufacturer for Rb 82 and/or Sr 82. As an alternative, use the Co-60 setting and the reading obtained divided by 0.548.
      Set the instrument to read in microcuries and record in the display.
    • Calculate the ratio (R) of Sr 85/Sr 82 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 the Sr 85/Sr 82 Ratio Factor from Table 2. Determine R using the following equation:

      [Sr 85]

      R= ———— on calibration date X Ratio Factor on the day (post-calibration) of measurement

      [Sr 82]

    • Use a correction factor (F) of 0.478 to compensate for the contribution of Sr 85 to the reading.
    • Calculate the amount of Sr 82 in the sample using the following equation:

      dose calibration reading (microCi)

      Sr 82 (microCi) = —————————————

      [1 + (R) (F)]

      Example: dose calibrator reading (microCi) = 0.8; Sr85/Sr82 ratio (R) = 1.48; correction factor (F) = 0.478.

      0.8

      Sr 82 (microCi) = ———————— = 0.47

      [1 + (1.48) (0.478)]

    • Determine if Sr 82 in the eluate exceeds an Alert or Expiration Limit by dividing the microCi 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 microCi or Sr 82; 50 mCi of Rb 82 E.O.E.

      0.47 microCi Sr 82

      ———————— = 0.0094 microCi/mCi Rb 82 (is above Alert Limit of 0.002; additional daily eluate 50 mCi Rb 82                                                       testing must be performed)

    • Determine if Sr 85 in the eluate exceeds an Alert or Expiration Limit by multiplying the result obtained in step 10 by (R) as calculated in step 7 (above).

      Example: 0.0094 x 1.48 = 0.014 microCi Sr 85/mCi Rb 82 (test result is below Alert and Expiration Limits)

    Use Table 1 to calculate the decay factor for Rb 82; step 4 (above).

    Table 1. Physical Decay Chart: Rb 82 half-life 75 seconds
    Seconds	Fraction Remaining	Seconds	Fraction Remaining
    0*	1	165	0.218
    15	0.871	180	0.19
    30	0.758	195	0.165
    45	0.66	210	0.144
    60	0.574	225	0.125
    75	0.5	240	0.109
    90	0.435	255	0.095
    105	0.379	270	0.083
    120	0.33	285	0.072
    135	0.287	300	0.063
    150	0.25
    *Elution time

    Use Table 2 to calculate the ratio (R) of Sr 85/Sr 82; step 7 (above).

    Table 2. Sr 85/Sr 82 Ratio Chart (Sr 85 T½= 65 days, Sr 82 T½= 25 days)
    Days	Ratio Factor	Days	Ratio Factor	Days	Ratio Factor
    0*	1	15	1.29	30	1.67
    1	1.02	16	1.31	31	1.7
    2	1.03	17	1.34	32	1.73
    3	1.05	18	1.36	33	1.76
    4	1.07	19	1.38	34	1.79
    5	1.09	20	1.41	35	1.82
    6	1.11	21	1.43	36	1.85
    7	1.13	22	1.46	37	1.88
    8	1.15	23	1.48	38	1.91
    9	1.17	24	1.51	39	1.95
    10	1.19	25	1.53	40	1.98
    11	1.21	26	1.56	41	2.01
    12	1.23	27	1.58	42	2.05
    13	1.25	28	1.61
    14	1.27	29	1.64
    *Day of calibration

    ,

    2.7 Eluate Testing Protocol for Infusion System Model 1700

    Use only additive-free 0.9% Sodium Chloride Injection for all elutions

    [see Warnings and Precautions ]

    .

    Observe aseptic technique throughout.

    Follow all instructions in the CardioGen-82 Infusion System Model 1700 Operator’s Manual for performing all eluate testing as described.

    Perform Mandatory Eluate Testing to determine Rb 82, Sr 82, and Sr 85 levels:

    • 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:
      • 14 L total elution volume has passed through the generator column, or
      • Sr 82 level reaches 0.002 microCi per mCi Rb 82, or
      • Sr 85 level reaches 0.02 microCi per mCi Rb 82.
    • The CardioGen-82 Infusion System Model 1700 will automatically indicate when alert limits have been reached, and will require that additional tests be performed, to facilitate the prompt detection of excessive levels of Sr 82 and/or Sr 85 should they occur.
    • These additional daily eluate tests will be performed at intervals determined by the day’s elution volume and will be enforced by the System software. Specifically, the infusion system will require the user to perform additional eluate testing after each 750 mL of elution volume when any Alert Limit parameter has been reached.

    Infusion System Calibration

    : Before administering Rubidium Chloride Rb 82 Injection to the first patient:

    After installation of a new generator and / or installation of a new CardioGen-82 Accessory Package, Item # 001710, perform the Rubidium Chloride Rb 82 Injection Dose Calibration (performed using an external dose calibrator).

    • Set a dose calibrator for Rb 82 as recommended by the manufacturer. Obtain the reading from the instrument in millicuries.
    • Following the prompts in the Graphical User Interface (GUI) for the CardioGen-82 Infusion System Model 1700, elute the generator with additive-free 0.9% Sodium Chloride Injection at a rate of 50 mL/min and collect the eluate in the stoppered vial specifically provided for use with the CardioGen-82 Infusion System Model 1700 (alternative vials, glass or plastic are not suitable). Note the exact time of end of elution (EOE).
    • Using the external dose calibrator, assay the eluate at exactly 2:30, 3:45, or 5:00 minutes after EOE.
    • Following the prompts in the GUI for the CardioGen-82 Infusion System Model 1700, enter the Rb 82 reading from the dose calibrator and the time since EOE.
    • The infusion system software will automatically calculate the Calibration Ratio.
      • If the ratio is within +/- 2% (0.98 to 1.02), the infusion system will allow acceptance of the calibration factor that was used for the elution.
      • If the ratio is not within +/- 2% (0.98 to 1.02), the system requires another calibration elution (steps 1 through 4).
    • Repeat steps 1 through 4 for a flow rate of 20 mL/min.

    Perform additional system calibration every 14 days.

    Daily Quality Control

    : Eluate (Strontium Level) Testing and Dose Constancy

    Each day, before administering Rubidium Chloride Rb 82 Injection, perform the following test, including Mandatory Eluate Testing:

    Daily Quality Control

    (performed on-board the CardioGen-82 Infusion System 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 detector well on the CardioGen-82 Infusion System Model 1700 and, following the prompts in the GUI for the infusion system, initiate the Daily Quality Control workflow.
    • The infusion system will automatically perform the Sr Detector Background Reading.
    • The infusion system will automatically perform the Generator Column Wash.
    • Strontium Level Test and Dose Constancy:
      • The infusion system will elute the generator with 50 mL of additive-free 0.9% Sodium Chloride Injection at a rate of 50 mL/min into the stoppered vial (which is specifically provided for use with the CardioGen-82 Infusion System Model 1700).
      • The Sr detector measures the Rb 82 and strontium in the 50 mL elution.
      • The infusion system software will automatically calculate the Sr 82 and Sr 85 levels on the day (post calibration) of the measurement using the ratio of Sr 85/Sr 82 on the day of calibration provided on the generator label, and using the full exponential decay calculation for each, accounting for the generator’s age.
      • Using the Rb 82 and strontium measurements, the infusion system software will automatically calculate microCi Sr 82/mCi Rb 82 and microCi Sr 85/mCi Rb 82. The GUI will automatically indicate if the results exceed Alert or Expiration Limits.
      • The infusion system software will automatically calculate Dose Constancy.
    • Constancy Check of the Sr detector: The infusion system GUI will prompt the user to perform the constancy check of the Sr detector.
      • Place the external constancy source in the detector well of the infusion system.
      • The infusion system software will automatically calculate the constancy of the Sr detector versus the external constancy source when instructed.

    ,

    2.8 Expiration Limits of CardioGen-82

    If using the Infusion System Model 510, stop use of CardioGen-82 once any one of the following Expiration Limits is reached:

    • A total elution volume of 17 L has passed through the generator column
    • 42 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

    If using the Infusion System Model 1700, the software will automatically indicate, and will stop use of CardioGen-82, once any one of the above Expiration Limits is reached.

    ) and Warnings and Precautions (

    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 ].

    )]

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.

• Dosing when using the Model 510 Infusion System: 1,480 MBq (40 mCi), with a range of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi) per rest or stress component of a procedure via intravenous infusion at 50 mL/min. (
  2.2 Dosing and Administration of Rubidium Chloride Rb 82 Injection

  Important Dosing and Administration Instructions

  • Observe aseptic techniques in all drug handling and administration.
  • Use CardioGen-82 with the CardioGen-82 Infusion System to elute and administer Rubidium Chloride Rb 82 Injection.
  • There are two infusion systems that are different in dosing, elution, and eluate testing. Ensure use of the correct infusion system when following the instructions for dosing, elution, and eluate testing.
  • 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 ]
    .
  • The minimum interval between the rest and stress doses is 10 minutes to allow sufficient Rb 82 decay.
  • Instruct patients to void as soon as a study is completed and as often as possible thereafter for at least one hour
    [see Warnings and Precautions ]
    .

  Dosing When Using the CardioGen-82 Model 510 Infusion System

  The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in adults is 1,480 MBq (40 mCi), with a range of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi), administered by intravenous infusion at 50 mL/minute through a catheter inserted into a large peripheral vein.

  Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure.

  Dosing When Using the CardioGen-82 Model 1700 Infusion System

  The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in adults is 10 MBq/kg to 30 MBq/kg actual body weight (0.27 mCi/kg to 0.81 mCi/kg) administered by intravenous infusion at 50 mL/minute or 20 mL/minute through a catheter inserted into a large peripheral vein.

  Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure.
  )
• Dosing when using the Model 1700 Infusion System: 10 MBq/kg to 30 MBq/kg actual body weight (0.27 mCi/kg to 0.81 mCi/kg) per rest or stress component of a procedure via intravenous infusion at 50 mL/minute or 20 mL/minute. (
  2.2 Dosing and Administration of Rubidium Chloride Rb 82 Injection

  Important Dosing and Administration Instructions

  • Observe aseptic techniques in all drug handling and administration.
  • Use CardioGen-82 with the CardioGen-82 Infusion System to elute and administer Rubidium Chloride Rb 82 Injection.
  • There are two infusion systems that are different in dosing, elution, and eluate testing. Ensure use of the correct infusion system when following the instructions for dosing, elution, and eluate testing.
  • 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 ]
    .
  • The minimum interval between the rest and stress doses is 10 minutes to allow sufficient Rb 82 decay.
  • Instruct patients to void as soon as a study is completed and as often as possible thereafter for at least one hour
    [see Warnings and Precautions ]
    .

  Dosing When Using the CardioGen-82 Model 510 Infusion System

  The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in adults is 1,480 MBq (40 mCi), with a range of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi), administered by intravenous infusion at 50 mL/minute through a catheter inserted into a large peripheral vein.

  Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure.

  Dosing When Using the CardioGen-82 Model 1700 Infusion System

  The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in adults is 10 MBq/kg to 30 MBq/kg actual body weight (0.27 mCi/kg to 0.81 mCi/kg) administered by intravenous infusion at 50 mL/minute or 20 mL/minute through a catheter inserted into a large peripheral vein.

  Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure.
  )
• Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure. (
  2.2 Dosing and Administration of Rubidium Chloride Rb 82 Injection

  Important Dosing and Administration Instructions

  • Observe aseptic techniques in all drug handling and administration.
  • Use CardioGen-82 with the CardioGen-82 Infusion System to elute and administer Rubidium Chloride Rb 82 Injection.
  • There are two infusion systems that are different in dosing, elution, and eluate testing. Ensure use of the correct infusion system when following the instructions for dosing, elution, and eluate testing.
  • 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 ]
    .
  • The minimum interval between the rest and stress doses is 10 minutes to allow sufficient Rb 82 decay.
  • Instruct patients to void as soon as a study is completed and as often as possible thereafter for at least one hour
    [see Warnings and Precautions ]
    .

  Dosing When Using the CardioGen-82 Model 510 Infusion System

  The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in adults is 1,480 MBq (40 mCi), with a range of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi), administered by intravenous infusion at 50 mL/minute through a catheter inserted into a large peripheral vein.

  Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure.

  Dosing When Using the CardioGen-82 Model 1700 Infusion System

  The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in adults is 10 MBq/kg to 30 MBq/kg actual body weight (0.27 mCi/kg to 0.81 mCi/kg) administered by intravenous infusion at 50 mL/minute or 20 mL/minute through a catheter inserted into a large peripheral vein.

  Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure.
  )
• The minimum interval between the rest and stress doses is 10 minutes to allow sufficient Rb 82 decay. (
  2.2 Dosing and Administration of Rubidium Chloride Rb 82 Injection

  Important Dosing and Administration Instructions

  • Observe aseptic techniques in all drug handling and administration.
  • Use CardioGen-82 with the CardioGen-82 Infusion System to elute and administer Rubidium Chloride Rb 82 Injection.
  • There are two infusion systems that are different in dosing, elution, and eluate testing. Ensure use of the correct infusion system when following the instructions for dosing, elution, and eluate testing.
  • 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 ]
    .
  • The minimum interval between the rest and stress doses is 10 minutes to allow sufficient Rb 82 decay.
  • Instruct patients to void as soon as a study is completed and as often as possible thereafter for at least one hour
    [see Warnings and Precautions ]
    .

  Dosing When Using the CardioGen-82 Model 510 Infusion System

  The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in adults is 1,480 MBq (40 mCi), with a range of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi), administered by intravenous infusion at 50 mL/minute through a catheter inserted into a large peripheral vein.

  Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure.

  Dosing When Using the CardioGen-82 Model 1700 Infusion System

  The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in adults is 10 MBq/kg to 30 MBq/kg actual body weight (0.27 mCi/kg to 0.81 mCi/kg) administered by intravenous infusion at 50 mL/minute or 20 mL/minute through a catheter inserted into a large peripheral vein.

  Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component of a procedure.
  )
• Start image acquisition 60 seconds to 90 seconds after completion of the infusion; if a longer circulation time is anticipated, wait for 120 seconds. Image acquisition is 5 minutes long. (
  2.3 Image Acquisition Instructions

  Rest Imaging

  • Administer a single dose of Rubidium Chloride Rb 82 Injection.
  • Start imaging 60 seconds to 90 seconds after completion of the first dose infusion and acquire images for 5 minutes.

  Stress Imaging

  • Begin the study at least 10 minutes after completion of the resting dose infusion, to allow for sufficient Rb 82 decay.
  • Administer a pharmacologic stress agent in accordance with its prescribing information.
  • After the administration of the pharmacologic stress agent, administer the second dose of Rubidium Chloride Rb 82 Injection at the time interval according to the prescribing information of the pharmacologic stress agent.
  • Start imaging 60 seconds to 90 seconds after completion of the second dose infusion and acquire images for 5 minutes.

  Rest and Stress Imaging

  • If a longer circulation time is anticipated (e.g., in a patient with severe left ventricular dysfunction), start imaging 120 seconds after the dose.
  • Acquisition may be started immediately post-injection if dynamic imaging is needed.
  )
• For radiation safety, infusion systems, elution instruction, eluate testing, dose delivery, and expiration limits of CardioGen-82, and radiation dosimetry see full prescribing information. (
  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 ].

  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.
  ,
  2.5 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 ]
    .
  • Prepare the 0.9 % Sodium Chloride Injection for use with the Saline Tag
    • Prepare the intravenous port in accordance with the approved prescribing information of the 0.9 % Sodium Chloride Injection.
    • The intravenous administration port of the 0.9% Sodium Chloride Injection container must be penetrated only one time.
    • Strap the saline tag provided with the CardioGen-82 Infusion System on the additive-free 0.9% Sodium Chloride Injection container and install on the CardioGen-82 Infusion System.
    • Once the container port closure is penetrated, it should remain installed on the CardioGen-82 Infusion System for its entire period of use. A maximum of 12 hours from the initial port closure penetration is permitted, after which the bag must be replaced for the next patient.
  • Allow at least 10 minutes between elutions for regeneration of Rb 82.
  • If the CardioGen-82 Infusion System Model 510 is used:
    • Discard the first 50 mL eluate each day the generator is eluted and employ proper safety precautions since the eluate contains radioactivity.
    • Maintain an on-going record of all eluate volumes (washing, testing, dosing volumes), including a summary of the cumulative volume of eluate from the generator.
    • Perform eluate testing according to the Eluate Testing Protocol for Infusion System Model 510
      [see Dosage and Administration ]
      .
  • If the CardioGen-82 Infusion System Model 1700 is used:
    • The system software 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 for Infusions System Model 1700
      [see Dosage and Administration ].
  • Stop using the generator when the expiration limits are reached
    [see Dosage and Administration ].
  • The maximum available activity of Rb 82 (dose delivery limit) will decrease as the generator ages. See Table 3 for the estimated maximum available Rb 82 activity as a function of generator age
    [see Dosage and Administration ].
  ,
  2.6 Eluate Testing Protocol for Infusion System Model 510

  Use only additive-free 0.9% Sodium Chloride Injection for all elutions

  [see Warnings and Precautions ]

  .

  Observe aseptic technique throughout.

  Follow all instructions in the CardioGen-82 Infusion System Model 510 Operator’s Manual for performing all eluate testing as described.

  Before administering Rubidium Chloride Rb 82 Injection to the first patient each day, perform the following testing:

  Strontium Alert Limits and Mandatory Eluate Testing:

  • Use an ionization chamber-type dose calibrator for eluate testing.
  • Daily, before administering Rubidium Chloride Rb 82 Injection to any patient, perform an eluate testing to determine Rb 82, Sr 82, and Sr 85 levels
  • Perform additional daily eluate tests after detecting any of the following Alert Limits:
    • 14 L total elution volume has passed through the generator column, or
    • Sr 82 level reaches 0.002 microCi per mCi Rb 82, or
    • Sr 85 level reaches 0.02 microCi per mCi Rb 82.
  • Perform the additional daily eluate tests at time points determined by the day’s elution volume; tests are performed every 750 mL.
    • For example, if an Alert Limit were reached and the clinical site eluted less than 750 mL from the generator during the day, then no additional eluate tests would have been performed that day.
    • If the same clinical site the next day eluted 1,500 mL from the generator, then the site would have performed three tests that day: 1) the required daily test that precedes any patient dosing, 2) a test at the 750 mL elution point, and 3) a test at the 1,500 mL elution points.
    • If a generator’s Alert Limit is reached, the clinical site performs the additional daily tests (at intervals of 750 mL) each subsequent day the generator is used. The additional tests are necessary to promptly detect excessive Sr 82 and/or Sr 85 in eluates.

  Rubidium Eluate Level Testing:

  • Set a dose calibrator for Rb 82 as recommended by the manufacturer or 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 0.9% Sodium Chloride Injection 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 0.9% Sodium Chloride Injection at a rate of 50 mL/min and collect the eluate in a stoppered glass vial (plastic containers are not suitable). Note the exact time of end of elution (E.O.E.).
  • Using the dose calibrator, determine the activity of Rb 82 and note the time of the reading. Correct the reading for decay to the E.O.E. using the appropriate decay factor for Rb 82 (see Table 1). Note: If the reading is taken 2 ½ minutes after end of elution, multiply the dose calibrator reading by 4 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 complete decay of Rb 82.
  • Measure the activity of the sample in a dose calibrator at the setting recommended by the manufacturer for Rb 82 and/or Sr 82. As an alternative, use the Co-60 setting and the reading obtained divided by 0.548.
    Set the instrument to read in microcuries and record in the display.
  • Calculate the ratio (R) of Sr 85/Sr 82 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 the Sr 85/Sr 82 Ratio Factor from Table 2. Determine R using the following equation:

    [Sr 85]

    R= ———— on calibration date X Ratio Factor on the day (post-calibration) of measurement

    [Sr 82]

  • Use a correction factor (F) of 0.478 to compensate for the contribution of Sr 85 to the reading.
  • Calculate the amount of Sr 82 in the sample using the following equation:

    dose calibration reading (microCi)

    Sr 82 (microCi) = —————————————

    [1 + (R) (F)]

    Example: dose calibrator reading (microCi) = 0.8; Sr85/Sr82 ratio (R) = 1.48; correction factor (F) = 0.478.

    0.8

    Sr 82 (microCi) = ———————— = 0.47

    [1 + (1.48) (0.478)]

  • Determine if Sr 82 in the eluate exceeds an Alert or Expiration Limit by dividing the microCi 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 microCi or Sr 82; 50 mCi of Rb 82 E.O.E.

    0.47 microCi Sr 82

    ———————— = 0.0094 microCi/mCi Rb 82 (is above Alert Limit of 0.002; additional daily eluate 50 mCi Rb 82                                                       testing must be performed)

  • Determine if Sr 85 in the eluate exceeds an Alert or Expiration Limit by multiplying the result obtained in step 10 by (R) as calculated in step 7 (above).

    Example: 0.0094 x 1.48 = 0.014 microCi Sr 85/mCi Rb 82 (test result is below Alert and Expiration Limits)

  Use Table 1 to calculate the decay factor for Rb 82; step 4 (above).

  Table 1. Physical Decay Chart: Rb 82 half-life 75 seconds
  Seconds	Fraction Remaining	Seconds	Fraction Remaining
  0*	1	165	0.218
  15	0.871	180	0.19
  30	0.758	195	0.165
  45	0.66	210	0.144
  60	0.574	225	0.125
  75	0.5	240	0.109
  90	0.435	255	0.095
  105	0.379	270	0.083
  120	0.33	285	0.072
  135	0.287	300	0.063
  150	0.25
  *Elution time

  Use Table 2 to calculate the ratio (R) of Sr 85/Sr 82; step 7 (above).

  Table 2. Sr 85/Sr 82 Ratio Chart (Sr 85 T½= 65 days, Sr 82 T½= 25 days)
  Days	Ratio Factor	Days	Ratio Factor	Days	Ratio Factor
  0*	1	15	1.29	30	1.67
  1	1.02	16	1.31	31	1.7
  2	1.03	17	1.34	32	1.73
  3	1.05	18	1.36	33	1.76
  4	1.07	19	1.38	34	1.79
  5	1.09	20	1.41	35	1.82
  6	1.11	21	1.43	36	1.85
  7	1.13	22	1.46	37	1.88
  8	1.15	23	1.48	38	1.91
  9	1.17	24	1.51	39	1.95
  10	1.19	25	1.53	40	1.98
  11	1.21	26	1.56	41	2.01
  12	1.23	27	1.58	42	2.05
  13	1.25	28	1.61
  14	1.27	29	1.64
  *Day of calibration
  ,
  2.7 Eluate Testing Protocol for Infusion System Model 1700

  Use only additive-free 0.9% Sodium Chloride Injection for all elutions

  [see Warnings and Precautions ]

  .

  Observe aseptic technique throughout.

  Follow all instructions in the CardioGen-82 Infusion System Model 1700 Operator’s Manual for performing all eluate testing as described.

  Perform Mandatory Eluate Testing to determine Rb 82, Sr 82, and Sr 85 levels:

  • 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:
    • 14 L total elution volume has passed through the generator column, or
    • Sr 82 level reaches 0.002 microCi per mCi Rb 82, or
    • Sr 85 level reaches 0.02 microCi per mCi Rb 82.
  • The CardioGen-82 Infusion System Model 1700 will automatically indicate when alert limits have been reached, and will require that additional tests be performed, to facilitate the prompt detection of excessive levels of Sr 82 and/or Sr 85 should they occur.
  • These additional daily eluate tests will be performed at intervals determined by the day’s elution volume and will be enforced by the System software. Specifically, the infusion system will require the user to perform additional eluate testing after each 750 mL of elution volume when any Alert Limit parameter has been reached.

  Infusion System Calibration

  : Before administering Rubidium Chloride Rb 82 Injection to the first patient:

  After installation of a new generator and / or installation of a new CardioGen-82 Accessory Package, Item # 001710, perform the Rubidium Chloride Rb 82 Injection Dose Calibration (performed using an external dose calibrator).

  • Set a dose calibrator for Rb 82 as recommended by the manufacturer. Obtain the reading from the instrument in millicuries.
  • Following the prompts in the Graphical User Interface (GUI) for the CardioGen-82 Infusion System Model 1700, elute the generator with additive-free 0.9% Sodium Chloride Injection at a rate of 50 mL/min and collect the eluate in the stoppered vial specifically provided for use with the CardioGen-82 Infusion System Model 1700 (alternative vials, glass or plastic are not suitable). Note the exact time of end of elution (EOE).
  • Using the external dose calibrator, assay the eluate at exactly 2:30, 3:45, or 5:00 minutes after EOE.
  • Following the prompts in the GUI for the CardioGen-82 Infusion System Model 1700, enter the Rb 82 reading from the dose calibrator and the time since EOE.
  • The infusion system software will automatically calculate the Calibration Ratio.
    • If the ratio is within +/- 2% (0.98 to 1.02), the infusion system will allow acceptance of the calibration factor that was used for the elution.
    • If the ratio is not within +/- 2% (0.98 to 1.02), the system requires another calibration elution (steps 1 through 4).
  • Repeat steps 1 through 4 for a flow rate of 20 mL/min.

  Perform additional system calibration every 14 days.

  Daily Quality Control

  : Eluate (Strontium Level) Testing and Dose Constancy

  Each day, before administering Rubidium Chloride Rb 82 Injection, perform the following test, including Mandatory Eluate Testing:

  Daily Quality Control

  (performed on-board the CardioGen-82 Infusion System 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 detector well on the CardioGen-82 Infusion System Model 1700 and, following the prompts in the GUI for the infusion system, initiate the Daily Quality Control workflow.
  • The infusion system will automatically perform the Sr Detector Background Reading.
  • The infusion system will automatically perform the Generator Column Wash.
  • Strontium Level Test and Dose Constancy:
    • The infusion system will elute the generator with 50 mL of additive-free 0.9% Sodium Chloride Injection at a rate of 50 mL/min into the stoppered vial (which is specifically provided for use with the CardioGen-82 Infusion System Model 1700).
    • The Sr detector measures the Rb 82 and strontium in the 50 mL elution.
    • The infusion system software will automatically calculate the Sr 82 and Sr 85 levels on the day (post calibration) of the measurement using the ratio of Sr 85/Sr 82 on the day of calibration provided on the generator label, and using the full exponential decay calculation for each, accounting for the generator’s age.
    • Using the Rb 82 and strontium measurements, the infusion system software will automatically calculate microCi Sr 82/mCi Rb 82 and microCi Sr 85/mCi Rb 82. The GUI will automatically indicate if the results exceed Alert or Expiration Limits.
    • The infusion system software will automatically calculate Dose Constancy.
  • Constancy Check of the Sr detector: The infusion system GUI will prompt the user to perform the constancy check of the Sr detector.
    • Place the external constancy source in the detector well of the infusion system.
    • The infusion system software will automatically calculate the constancy of the Sr detector versus the external constancy source when instructed.
  ,
  2.8 Expiration Limits of CardioGen-82

  If using the Infusion System Model 510, stop use of CardioGen-82 once any one of the following Expiration Limits is reached:

  • A total elution volume of 17 L has passed through the generator column
  • 42 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

  If using the Infusion System Model 1700, the software will automatically indicate, and will stop use of CardioGen-82, once any one of the above Expiration Limits is reached.
  ,
  2.9 Dose Delivery Limit of CardioGen-82

  The maximum available Rb 82 activity per elution (dose delivery limit) will decrease as the generator ages. Table 3 provides an estimate of the maximum available activity of Rb 82 as a function of generator age.

  Table 3. Maximum Available Rb 82 Activity Based on Generator Age 1
  Generator Age (days) 2	Maximum Rb 82 Activity per Elution
  0-17	60 mCi (2,220 MBq)
  24	50 mCi (1,850 MBq)
  32	40 mCi (1,480 MBq)
  42	30 mCi (1,110 MBq)
  1Estimate is based on a 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, a 90 mCi (3,330 MBq) generator and a 150 mCi (5,550 MBq) generator will reach a delivery limit <60 mCi at ≥ 14 days and ≥ 33 days, respectively.
  ,
  2.10 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 4.

  Table 4. Estimated Absorbed Radiation Dose Coefficient in Adults
  Organa,b	Rb 82 (Average for Rest and Stress) mrem/mCi (microSv/3.7MBq)c	Sr 82 mrem/microCi (microSv/3.7kBq)c	Sr 85 mrem/microCi (microSv/3.7kBq)c
  Adrenals	7.56	10.6	5.03
  Bone – Osteogenic cells Bone Surface	1.86 ----	--- 107	--- 9.81
  Brain	0.6	8.29	2.96
  Breast	0.82	7.03	1.72
  Gall Bladder Wall	3.17	8.47	2.82
  Heart Wall	16.5	8.18	2.67
  Kidneys	20.04	9.18	2.5
  Liver	4.2	8.10	2.5
  Lower Large Intestine Wall	2.84	51.8	5.14
  Lungsd	10.7	8.25	2.84
  Muscles	1.29	8.14	2.66
  Ovaries	1.41	10.2	4.29
  Pancreas	8.85	9.1	3.46
  Red Marrow	1.19	91	9.84
  Skin	1.14	7.03	1.75
  Small Intestine	4.76	9.62	4.03
  Spleen	6.61	8.1	2.54
  Stomach	8.14	7.84	2.26
  Testes	0.82	7.25	1.7
  Thymus	1.49	7.84	2.33
  Thyroid	6.11	8.07	2.57
  Upper Large Intestine	5.94	23.7	3.62
  Urinary Bladder Wall	1.61	21.9	2.9
  Uterus	3.72	9.14	3.32
  Total Body	1.77	Not calculated	Not calculated
  Effective Dosee	4.74f	23.4	4.03
  aRb 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. bSr 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. cTo convert to SI units, insert the dose coefficient into the formula in parentheses, e.g. for adrenals 7.56 mrem/mCi = 7.56 microSv/37 MBq = 2.04 x 10-13Sv/Bq. dCalculated from ICRP 66 eCalculated from ICRP 60 fStress phase only
  )

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 a hydrous stannic oxide column.

Lactation: Do not resume breastfeeding until at least one hour after administration of Rubidium Chloride Rb 82 Injection. (