CARDIOGEN-82 Solution for injection Ref.[10196] Active ingredients: Rubidium ⁸²Rb chloride

2.1 Radiation Safety – Drug Handling

Rubidium Rb 82 is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure during administration [See Warnings and Precautions (5.5)].

• Use only additive-free 0.9% Sodium Chloride Injection USP to elute the generator [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].
• Limit the use of radiopharmaceuticals to physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.
• Wear waterproof gloves and effective shielding when handling rubidium Rb 82 chloride injection and the infusion system.
• Observe aseptic techniques in all drug handling.
• Visually inspect the drug for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer eluate from the generator if there is any evidence of foreign matter.

2.2 Rubidium Rb 82 Chloride Injection Dosage

The recommended adult single dose of rubidium Rb 82 chloride injection per rest or stress component of a PET myocardial perfusion imaging (MPI) procedure is 1,480 MBq (40 mCi) with a range of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi).

• Do not exceed a single dose of 2,220 MBq (60 mCi).
• Use the lowest dose necessary, consistent with the goal of as low as reasonably achievable (ALARA), to obtain adequate cardiac visualization. The choice of dosage and infusion rate should be made at the discretion of the physician performing the Rb 82 PET myocardial perfusion imaging scan, based on his/her consideration of multiple factors, including patient body mass, 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 the single dose at 50 mL/minute, or at 20 mL/minute (CardioGen-82 Infusion System Model 1700 only), through a catheter inserted into a large peripheral vein; do not to exceed a total infusion volume of 100 mL.
• Instruct patients to void as soon as a study is completed and as often as possible thereafter for at least one hour.
• The maximum available activity (delivery limit) will decrease as the generator ages [see Dosage and Administration (2.9)].

2.3 Image Acquisition Guidelines

Administer two separate single doses to complete rest and stress myocardial perfusion imaging as follows:

For Rest Imaging:

• Administer a single (“rest”) rubidium Rb 82 chloride dose;
• Start imaging 60 to 90 seconds after completion of the infusion of the rest dose, and acquire images for 5 minutes.

For Stress Imaging:

• Begin the study 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 Rb 82 at the time interval according to the prescribing information of the pharmacologic stress agent;
• Start imaging 60 to 90 seconds after completion of the stress Rb 82 chloride dose infusion, and acquire images for 5 minutes.

For Both 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 rest dose.
• Acquisition may be started immediately post-injection if dynamic imaging is needed.

2.4 Infusion System

• Use CardioGen-82 only with the CardioGen-82 Infusion System Model 510 or the CardioGen-82 Infusion System Model 1700, which are specifically designed for use with the generator and capable of accurate measurement and delivery of doses of rubidium Rb 82 chloride injection.
  • If using the CardioGen-82 Infusion System Model 510, refer to the Eluate Testing Protocol in Section 2.6 [see Dosage and Administration (2.6)].
  • If using the CardioGen-82 Infusion System Model 1700, refer to the Eluate Testing Protocol in Section 2.7 [see Dosage and Administration (2.7)].
• Follow instructions in the CardioGen-82 Infusion System Model 510 or Model 1700 Operator’s Manual for the set up and intravenous infusion 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 doses of 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% Sodium Chloride Injection USP to elute the generator [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].
• Prepare the 0.9% Sodium Chloride Injection USP for use with the Saline Tag
  • Prepare the intravenous port in accordance with the DOSAGE AND ADMINISTRATION section of the approved prescribing information of the 0.9% Sodium Chloride Injection USP.
  • The intravenous administration port of the sodium chloride 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 USP 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. If the CardioGen-82 Infusion System Model 1700 is used, the system will automatically discard the first 50 mL of eluate each day the generator is eluted.
• If the CardioGen-82 Infusion System Model 510 is used, 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. If the CardioGen-82 Infusion System Model 1700 is used, the system software automatically 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.

2.6 CardioGen-82 Infusion System Model 510 Eluate Testing Protocol

Use only additive-free 0.9% Sodium Chloride Injection USP for all elutions [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].

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 Rb 82 chloride 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 Rb 82 chloride 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 µCi per mCi Rb 82, or
  • Sr 85 level reaches 0.02 µCi 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 Sodium Chloride Injection USP 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 USP 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 (postcalibration) 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:

R = [Sr 85] / [Sr 82] on calibration date X Ratio Factor on the day (post-calibration) of measurement

• 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:

Sr 82 (μCi) = dose calibration reading (μCi) / [1 + (R) (F)]
Example: dose calibrator reading (µCi) = 0.8; Sr85/Sr82 ratio (R) = 1.48; correction factor (F) = 0.478.
Sr 82 (μCi) = 0.8 / [1 + (1.48)(0.478)] = 0.47

• Determine if Sr 82 in the eluate exceeds an Alert or Expiration Limit by dividing the µCi 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 µCi or Sr 82; 50 mCi of Rb 82 E.O.E.
0.47 μCi Sr 82 / 50 mCi Rb 82 = 0.0094 μCi/mCi Rb 82 (is above Alert Limit of 0.002; additional daily eluate 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 × 1.48 = 0.014 µCi 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:

* 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 T _½ = 65 days, Sr 82 T _½ = 25 days):

* Day of calibration

2.7 CardioGen-82 Infusion System Model 1700 Eluate Testing Protocol

Use only additive-free 0.9% Sodium Chloride Injection USP for all elutions [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].

Observe aseptic technique throughout.

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

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

• Daily – Before administering rubidium Rb 82 chloride 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 µCi per mCi Rb 82, or
  • Sr 85 level reaches 0.02 µCi 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 Rb 82 chloride 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 Rb 82 Chloride 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 USP 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 Rb 82 chloride 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 USP 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 µCi Sr 82/mCi Rb 82 and µCi 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 CardioGen-82 Expiration

If using the CardioGen-82 Infusion System Model 510, stop use of the CardioGen-82 generator once any one of the following Expiration Limits is reached. If using the CardioGen-82 Infusion System Model 1700, the software will automatically indicate, and will stop use of, the CardioGen-82 generator once any one of the following Expiration Limits is reached.

• A total elution volume of 17 L has passed through the generator column, or
• 42 days post calibration date, or
• An eluate Sr 82 level of 0.01 µCi /mCi Rb 82, or
• An eluate Sr 85 level of 0.1 µCi /mCi Rb 82.

2.9 CardioGen-82 Dose Delivery Limit

The maximum available activity (delivery limit) will decrease as the generator ages. Certain doses, including the maximum recommended dose [60 mCi (2,220 MBq)] are not achievable for the entire shelf-life of the generator. Table 3 provides an estimate of the maximum available activity of Rubidium Rb 82 (Delivery Limit) as a function of generator age.

Table 3. Rubidium Rb 82 Dose Delivery Limit Based on GeneratorAge¹:

¹ Estimate is based on a 100 mCi (3,700 MBq) Sr 82 generator at calibration.
² Generator age at which delivery limit is reached varies with generator activity at release. For example, a 90 mCi (3,330 MBq) generator and a 150 mCi (5,550 MBq) generator will reach a delivery limit <60 mCi at ≥14 days and ≥33 days, respectively.

2.10 Radiation Dosimetry

The estimated absorbed radiation doses for Rb 82, Sr 82, and Sr 85 from an intravenous injection of rubidium Rb 82 chloride are shown in Table 4.

Table 4. Adult Absorbed Radiation Dose Coefficient:

^a Rb 82 doses are averages of rest and stress dosimetry data (see Senthamizhchelvan et al.^1,2). To calculate organ doses (mrem) from Rb 82, multiply the dose coefficient for each organ by the administered activity in mCi.
^b Sr 82 and Sr 85 doses are calculated using software package DCAL and ICRP dose coefficients. To calculate organ doses (mrem) attributable to Sr 82, and Sr 85, multiply the dose coefficients by the calculated amounts of strontium in µCi.^3
c To convert to SI units, insert the dose coefficient into the formula in parentheses, e.g. for adrenals 7.56 mrem/mCi = 7.56 µSv/37 MBq = 2.04 × 10^-13 Sv/Bq.
^d Calculated from ICRP 66
^e Calculated from ICRP 60
^f Stress phase only

• Store the generator at 20° to 25°C (68° to 77°F) [See USP].
• Receipt, transfer, possession, storage, disposal or use of this product is subject to the radioactive material regulations and licensing requirements of the U.S. Nuclear Regulatory Commission (NRC), Agreement States or Licensing States as appropriate. Do not dispose of the generator in regular refuse systems.
• For questions about the disposal of the CardioGen-82 generator, contact Bracco Diagnostics Inc. at 1-800-447-6883, option 3.