CardioGen-82 by is a Prescription medication manufactured, distributed, or labeled by Bracco Diagnostics Inc, GE HEALTHCARE INC., BWXT ITG Canada, Inc.. Drug facts, warnings, and ingredients follow.
Exposure with Failure to Follow the Eluate Testing Protocol
Excess radiation exposure occurs when the levels of Sr 82 or Sr 85 in the rubidium Rb 82 chloride injection exceed limits. (5.2)
|Boxed Warning, HIGH LEVEL RADIATION EXPOSURE WITH USE OF INCORRECT ELUENT AND FAILURE TO FOLLOW THE ELUATE TESTING PROTOCOL||04/2019|
|Dosage and Administration, Directions for Eluting|
|Rubidium Rb 82 Chloride Injection (2.4)||04/2019|
|Warnings and Precautions, High Level Radiation Exposure with Use of Incorrect Eluent (5.1)||04/2019|
CardioGen-82 is a closed system used to produce rubidium Rb 82 chloride injection for intravenous use. Rubidium Rb 82 chloride injection is a radioactive diagnostic agent indicated for Positron Emission Tomography (PET) imaging of the myocardium under rest or pharmacologic stress conditions to evaluate regional myocardial perfusion in adult patients with suspected or existing coronary artery disease. (1)
CardioGen-82 consists of strontium Sr 82 adsorbed on a hydrous stannic oxide column with an activity of 90-150 millicuries Sr 82 at calibration time. (3)
CardioGen-82 is contraindicated if a solution other than additive free 0.9% Sodium Chloride Injection USP has been used to elute the generator at any time. (4)
To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc at 1-800-257-5181 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch (6)
See 17 for PATIENT COUNSELING INFORMATION.
CardioGen-82 is a closed system used to produce rubidium Rb 82 chloride injection for intravenous administration. Rubidium Rb 82 chloride injection is indicated for Positron Emission Tomography (PET) imaging of the myocardium under rest or pharmacologic stress conditions to evaluate regional myocardial perfusion in adult patients with suspected or existing coronary artery disease.
Use CardioGen-82 only with an infusion system specifically designed for use with the generator and capable of accurate measurement and delivery of doses of rubidium Rb 82 chloride injection. Follow instructions in the Infusion System User’s Guide for the set up and intravenous infusion of rubidium Rb 82 chloride injection dose(s).
Physical Decay Chart: Rb 82 half-life 75 seconds
|*Day of calibration|
Sr 85/Sr 82 Ratio Chart (Sr 85 T ½ = 65 days, Sr 82 ½ = 25 days)
|Days||Ratio Factor||Days||Ratio Factor||Days||Ratio Factor|
|aRb 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
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 μCi.3
cTo 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 x 10-13 Sv/Bq.
dCalculated from ICRP 66
eCalculated from ICRP 60
fStress phase only
|Table 3 Adult Absorbed Radiation Dose Coefficient|
(Average for Rest and Stress)
|Bone – Osteogenic cells||1.86||---||---|
|Gall Bladder Wall||3.17||8.47||2.82|
|Lower Large Intestine Wall||2.84||51.8||5.14|
|Upper Large Intestine||5.94||23.7||3.62|
|Urinary Bladder Wall||1.61||21.9||2.90|
|Total Body||1.77||Not Calculated||Not Calculated|
Strictly adhere to the eluate testing protocol to minimize radiation exposure to the patient. Stop using the rubidium generator when the expiration limits are reached [see Dosage and Administration (2.5) and (2.6)].
Pharmacologic induction of cardiovascular stress may be associated with serious adverse reactions such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction, and cerebrovascular events. Perform pharmacologic stress testing in accordance with the pharmacologic stress agent’s prescribing information and only in the setting where cardiac resuscitation equipment and trained staff are readily available.
Patients with congestive heart failure or the elderly may experience a transitory increase in circulatory volume load. Observe these patients during infusion and for several hours following rubidium chloride injection administration to detect delayed hemodynamic disturbances.
Rubidium Rb 82 chloride injection, similar to other radiopharmaceuticals, contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Use the lowest dose of rubidium Rb 82 chloride injection necessary for imaging and ensure safe handling to protect the patient and health care worker [see Dosage and Administration (2.2) and (2.3)]. Encourage patients to void as soon as a study is completed and as often as possible thereafter for at least one hour.
The following serious adverse reactions have been identified during postapproval use of CardioGen-82. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
High level radiation exposure to the bone marrow has occurred in some patients due to Sr 82 and Sr 85 breakthrough in the eluate when an incorrect solution was used to elute the rubidium Rb 82 generator [see Boxed Warning and Warnings and Precautions (5.1)].
Excess radiation exposure has occurred in some patients who received rubidium Rb 82 chloride injections at clinical sites where generator eluate testing appeared insufficient [see Boxed Warning, Warnings and Precautions (5.2), and Dosage and Administration (2.5)].
There are no data available on the use of rubidium Rb 82 chloride in pregnant women. Animal reproductive studies have not been conducted with rubidium Rb 82 chloride injection. However, all radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering rubidium Rb 82 chloride injection administration to a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from rubidium Rb 82 and the gestational timing of exposure.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
There is no information regarding the presence of Rb 82 chloride in human milk, the effects on the breastfed infant or the effects on milk production. Due to the short half-life of rubidium Rb 82 (75 seconds), exposure of a breastfed infant through breast milk can be minimized by temporary discontinuation of breastfeeding [See Clinical Considerations]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rubidium Rb 82 chloride injection, any potential adverse effects on the breastfed child from Rb 82 or from the underlying maternal condition.
Exposure to Rb 82 chloride through breast milk can be minimized if breastfeeding is discontinued when Rb 82 chloride injection is administered. Do not resume breastfeeding until at least one hour after completion of rubidium Rb 82 chloride injection infusion.
In elderly patients with a clinically important decrease in cardiac function, lengthen the delay between infusion and image acquisition [see Dosage and Administration (2.2)]. Observe for the possibility of fluid overload [see Warnings and Precautions (5.4)].
Reductions in renal function are not anticipated to alter clearance of rubidium Rb 82 chloride injection because Rb 82 decays to stable Kr 82 with a half-life of 75 seconds and Kr 82 is exhaled through the lungs.
CardioGen-82 contains accelerator-produced Sr 82 adsorbed on stannic oxide in a lead-shielded column and provides a means for obtaining sterile nonpyrogenic solutions of rubidium Rb 82 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 the
When eluted at a rate of 50 mL/minute, each generator eluate at the end of elution should not contain more than 0.02 microcurie of Sr 82 and not more than 0.2 microcurie of Sr 85 per millicurie of rubidium Rb 82 chloride injection, and not more than 1 microgram of tin per mL of eluate.
Rb 82 decays by positron emission and associated gamma emission with a physical half-life of 75 seconds.4 Table 4 shows the annihilation photons released following positron emission which are useful for detection and imaging studies.
The decay modes of Rb 82 are: 95.5% by positron emission, resulting in the production of annihilation radiation, i.e., two 511 keV gamma rays; and 4.5% by electron capture, resulting in the emission of “prompt” gamma rays of predominantly 776.5 keV. Both decay modes lead directly to the formation of stable Kr 82.4
Principal Radiation Emission Data
|Mean Percent||Mean Energy|
|Annihilation photons (2)||191.01||511 (each)|
The specific gamma ray constant for Rb 82 is 6.1 R/hour-millicurie at 1 centimeter. The first half-value layer is 0.7 centimeter of lead (Pb). Table 5 shows a range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of lead.5 For example, the use of a 7.0 centimeter thickness of Pb will attenuate the radiation emitted by a factor of about 1,000.
Radiation Attenuation by Lead Shielding
|Shield Thickness (Pb) cm||Attenuation Factor|
Physical Decay Chart: Sr 82 half-life 25 days
To correct for physical decay of Rb 82, Table 1 shows the fraction of Rb 82 remaining in all 15 second intervals up to 300 seconds after time of calibration [see Dosage and Administration (2.5)].
Rb 82 is analogous to potassium ion (K+) in its biochemical behavior and is rapidly extracted by the myocardium proportional to the blood flow. Rb+ participates in the sodium-potassium (Na+/K+) ion exchange pumps that are present in cell membranes. The intracellular uptake of Rb 82 requires maintenance of ionic gradient across cell membranes. Rb 82 radioactivity is increased in viable myocardium reflecting intracellular retention, while the tracer is cleared rapidly from necrotic or infarcted tissue.
human studies, myocardial activity was noted within the first minute
after peripheral intravenous injection of Rb 82. When areas of infarction
or ischemia are present in the myocardium, they are visualized within
2-7 minutes after injection as photon-deficient, or “cold”, areas
on the myocardial scan.
In patients with reduced cardiac function, transit of the injected dose from the peripheral infusion site to the myocardium may be delayed [see Dosage and Administration (2.2)].
Blood flow brings Rb 82 to all areas of the body during the first pass of circulation. Accordingly, visible uptake is also observed in other highly vascularized organs, such as the kidneys, liver, spleen and lungs.
With a physical half-life of 75 seconds, Rb 82 is very rapidly converted by radioactive decay into a trace amount of stable Kr 82 gas, which is passively expired by the lungs. Renal and hepatic excretion is not anticipated to play an essential role in Rb 82 elimination, although some of the Rb 82 dose may be excreted in the urine prior to radioactive decay.
In a descriptive, prospective, blinded image interpretation study6 of adult patients with known or suspected coronary artery disease, myocardial perfusion deficits in stress and rest PET images obtained with ammonia N 13 (n = 111) or rubidium Rb 82 chloride (n = 82) were compared to changes in stenosis flow reserve (SFR) as determined by coronary angiography. PET perfusion defects at rest and stress for seven cardiac regions (anterior, apical, anteroseptal, posteroseptal, anterolateral, posterolateral, and inferior walls) were graded on a scale of 0 (normal) to 5 (severe). Values for stenosis flow reserve, defined as flow at maximum coronary vasodilatation relative to rest flow, ranged from 0 (total occlusion) to 5 (normal). With increasing impairment of flow reserve, the subjective PET defect severity increased. A PET defect score of 2 or higher was positively correlated with flow reserve impairment (SFR<3).
A systematic review of published literature was conducted using pre-defined inclusion/exclusion criteria which resulted in identification of 10 studies evaluating the use of Rb 82 PET myocardial perfusion imaging (MPI) for the identification of coronary artery disease as defined by catheter-based angiography. In these studies, the patient was the unit of analysis and 50% stenosis was the threshold for clinically significant coronary artery disease (CAD). Of these 10 studies, 9 studies were included in a meta-analysis for sensitivity (excluding one study with 100% sensitivity) and 7 studies were included in a meta-analysis of specificity (excluding 3 studies with 100% specificity). A random effects model yielded overall estimates of sensitivity and specificity of 92% (95% CI: 89% to 95%) and 81% (95% CI: 76% to 86%), respectively. The use of meta-analysis in establishing performance characteristics is limited, particularly by the possibility of publication bias (positive results being more likely to be published than negative results) which is difficult to detect especially when based on a limited number of small studies.
CardioGen-82® (rubidium Rb 82 generator) consists of Sr 82 adsorbed on a hydrous stannic oxide column with an activity of 90-150 millicuries Sr 82 at calibration time. A lead shield surrounded by a labeled plastic container encases the generator. The container label provides complete assay data for each generator. Directions for determining the activity of Rb 82 eluted from the generator are described above [see Dosage and Administration (2.5)]. Use CardioGen-82 (rubidium Rb 82 Generator) only with an appropriate, properly calibrated infusion system labeled for use with the generator.
Receipt, transfer, handling, possession or use of this product is subject to the radioactive material regulations and licensing requirements of the U.S. Nuclear Regulatory Commission, Agreement States or Licensing States as appropriate.
Licensee personnel should monitor the amount of radioactivity present within the generator prior to its disposal. Do not dispose of the generator in regular refuse systems. Store and/or dispose of the generator in accordance with the conditions of NRC radioactive materials license pursuant to 10 CFR, Part 20, or equivalent conditions pursuant to Agreement State Regulation. For questions about the disposal of the CardioGen-82 generator, contact Bracco Diagnostics Inc. at 1-800-447-6883, option 3.
rubidium chloride rb-82 injection, solution
|Labeler - Bracco Diagnostics Inc (849234661)|
|Registrant - Bracco Diagnostics Inc (849234661)|
|GE HEALTHCARE INC.||154129886||MANUFACTURE(0270-0091)|
|BWXT ITG Canada, Inc.||203794193||API MANUFACTURE(0270-0091)|