CARDIOGEN-82- rubidium chloride rb-82 injection, solution
Bracco Diagnostics Inc
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CARDIOGEN-82 safely and effectively. See full prescribing information for CARDIOGEN-82.
CARDIOGEN-82® (rubidium Rb 82 generator)
To produce rubidium Rb 82 chloride injection, for intravenous use
Initial U.S. Approval: 1989
WARNING: HIGH LEVEL RADIATION EXPOSURE WITH USE OF INCORRECT ELUENT AND FAILURE TO FOLLOW THE ELUATE TESTING PROTOCOL
Please see full prescribing information for complete boxed warning
High Level Radiation
Exposure with Use of Incorrect Eluent
Exposure with Failure to Follow the Eluate Testing Protocol
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
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)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
CardioGen-82 consists of strontium Sr 82 adsorbed on a hydrous stannic oxide column with an activity of 3,330 MBq to 5,550 MBq (90 millicuries to 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)
WARNINGS AND PRECAUTIONS
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)
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: HIGH LEVEL RADIATION EXPOSURE WITH USE OF INCORRECT ELUENT AND FAILURE TO FOLLOW THE ELUATE TESTING PROTOCOL
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Radiation Safety - Drug Handling
2.2 Rubidium Rb 82 Chloride Injection Dosage
2.3 Image Acquisition Guidelines
2.4 Infusion System
2.5 Directions for Eluting Rubidium Rb 82 Chloride Injection
2.6 CardioGen-82 Infusion System Model 510 Eluate Testing Protocol
2.7 CardioGen-82 Infusion System Model 1700 Eluate Testing Protocol
2.8 CardioGen-82 Expiration
2.9 CardioGen-82 Dose Delivery Limit
2.10 Radiation Dosimetry
3 DOSAGE FORMS AND STRENGTHS
5 WARNINGS AND PRECAUTIONS
5.1 High Level Radiation Exposure with Use of Incorrect Eluent
5.2 Excess Radiation Exposure with Failure to Follow Eluate Testing Protocol
5.3 Risk Associated with Pharmacologic Stress
5.4 Volume Overload
5.5 Cumulative Radiation Exposure: Long-Term Risk of Cancer
6 ADVERSE REACTIONS
6.1 Post marketing Experience
8 USE IN SPECIFIC POPULATIONS
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
11.1 Chemical Characteristics
11.2 Physical Characteristics
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
17 PATIENT COUNSELING INFORMATION
Radiation Exposure with Use of Incorrect Eluent
Patients are exposed to high radiation levels when the CardioGen-82 generator is eluted with the incorrect eluent due to high Sr 82 and Sr 85 breakthrough levels [see Warnings and Precautions (5.1)]
Radiation 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 specified limits [see Warnings and Precautions (5.2)]
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.
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)].
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).
Administer two separate single doses to complete rest and stress myocardial perfusion imaging as follows:
For Both Rest and Stress Imaging:
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:
Rubidium Eluate Level Testing:
Use Table 1 to calculate the decay factor for Rb 82; step 4 (above).
Physical Decay Chart: Rb 82 half-life 75 seconds
Use Table 2 to calculate the ratio (R) of Sr 85/Sr 82; step 7 (above).
|*Day of calibration|
Sr 85/Sr 82 Ratio Chart (Sr 85 T ½ = 65 days, Sr 82 T ½ = 25 days)
|Days||Ratio Factor||Days||Ratio Factor||Days||Ratio Factor|
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:
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).
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):
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.
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.
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.
|Table 3 Rubidium Rb 82 Dose Delivery Limit Based on Generator Age1|
|Generator Age (days)2||Maximum Rubidium Dose (Delivery Limit)|
|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)|
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.
|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 4 Adult Absorbed Radiation Dose Coefficient|
(Average for Rest and Stress)
mrem/mCi (µSv/3.7 MBq)c
|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|
CardioGen-82 is a closed system used to produce rubidium Rb 82 chloride injection for intravenous use. CardioGen-82 consists of strontium Sr 82 adsorbed on a hydrous stannic oxide column with an activity of 3,330 MBq to 5,550 MBq (90 millicuries to 150 millicuries) Sr 82 at calibration time.
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. Immediately stop the patient infusion and permanently discontinue the use of the affected CardioGen-82 generator whenever the incorrect eluent is used [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]
Use only additive free 0.9% Sodium Chloride Injection USP to elute the generator. Apply the provided saline tag to the additive free 0.9% Sodium Chloride Injection USP container before use. Additives present in other solutions (particularly calcium ions) 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 [Dosage and Administration (2.1, 2.5, and 2.6, 2.7)].
Immediately stop the patient infusion and discontinue use of the affected CardioGen-82 generator if the incorrect eluent is used and evaluate the patient’s radiation absorbed dose and monitor for the effects of radiation to critical organs such as bone marrow. When solutions containing calcium ions are used to elute the generator, high levels of radioactivity are present in any subsequent eluate, even with the use of additive free 0.9% Sodium Chloride Injection USP. [see Boxed Warning, Dosage and Administration (2.10) and Contraindications (4)].
Excess radiation exposure occurs when the Sr 82 and Sr 85 levels in rubidium Rb 82 chloride injections exceed the specified generator eluate limits.
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 (2.6, 2.7) and (2.8)].
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.
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 (2.1) and (2.2)]. Encourage patients to void as soon as a study is completed and as often as possible thereafter for a 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 (2.6 or 2.7)].
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 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.
Rubidium Rb 82 chloride injection safety and effectiveness in pediatric patients have not been established.
In elderly patients with a 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)].
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 generator. 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 5 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 6 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|
Sr 82 (half-life of 25 days (600 hrs.)) decays to Rb 82. To correct for physical decay of Sr 82, Table 7 shows the fractions that remain at selected intervals after the time of calibration.
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 (2.6, 2.7)].
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.
In 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 (2.3)].
Blood flow brings Rb 82 to all areas of the body during the first pass of circulation. Accordingly, visible uptake is also observed in other highly vascularized organs, such as the kidneys, liver, spleen and lungs.
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, posterolateral, 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 system 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), used to produce rubidium Rb 82 chloride injection, consists of Sr 82 adsorbed on a hydrous stannic oxide column with an activity of 3,330 MBq to 5,550 MBq (90 millicuries to 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. Use CardioGen-82 (rubidium Rb 82 Generator) only with an appropriate, properly calibrated infusion system labeled for use with the generator.
Advise a pregnant woman of the potential risk to a fetus [see Use in Specific Populations (8.1)].
Advise lactating women that exposure to Rb-82 chloride through breast milk can be minimized if breastfeeding is discontinued when Rb 82 chloride injection is administered. Advise lactating women not to resume breastfeeding for at least one hour after completion of rubidium Rb 82 infusion [see Use in Specific Populations (8.2)].
Instruct patients to void after completion of each image acquisition session and as often as possible for one hour after completion of the PET scan [see Warnings and Precautions (5.5)].
Bracco Diagnostics Inc.
Monroe Twp, NJ 08831
By GE Healthcare
South Plainfield, NJ 07080
CardioGen-82® Rubidium 82 Generators, Infusion Systems, and Accessories contain proprietary technology covered by one or more patents listed at www.braccoimaging.com/us-en/patents.
Rubidium Rb 82 Generator
rubidium chloride rb-82 injection, solution
|Labeler - Bracco Diagnostics Inc (849234661)|
|Registrant - Bracco Diagnostics Inc (849234661)|
|GE HEALTHCARE INC.||154129886||MANUFACTURE(0270-0091)|
|BWXT Medical Ltd||203794193||API MANUFACTURE(0270-0091)|