CARDIOGEN-82- rubidium chloride rb-82 injection, solution
BRACCO DIAGNOSTICS INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese 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: UNINTENDED STRONTIUM-82 (Sr-82)
AND STRONTIUM-85 (Sr-85) RADIATION EXPOSURE
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Unintended 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 (5.1)]
Perform generator eluate tests:
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).
The recommended adult single dose of rubidium Rb 82 chloride injection is 1480 MBq (40 mCi) with a range of 1110-2220 MBq (30-60 mCi).
Administer two separate single doses to complete rest and stress myocardial perfusion imaging as follows:
Use additive-free sodium chloride injection USP for all elutions. Apply aseptic technique throughout.
Before administering rubidium Rb 82 chloride injection to the first patient each day, perform the following test:
Strontium Alert Limits and Mandatory Eluate Testing:
Perform the additional daily eluate tests at time points determined by the day’s elution volume; tests are performed every 750 mL.
Rubidium Eluate Level Testing:
*Elution time | |||
TABLE 1 Physical Decay Chart: Rb-82 half-life 75 seconds |
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Seconds | Fraction Remaining | Seconds | Fraction Remaining |
0* | 1.000 | 165 | 0.218 |
15 | 0.871 | 180 | 0.190 |
30 | 0.758 | 195 | 0.165 |
45 | 0.660 | 210 | 0.144 |
60 | 0.574 | 225 | 0.125 |
75 | 0.500 | 240 | 0.109 |
90 | 0.435 | 255 | 0.095 |
105 | 0.379 | 270 | 0.083 |
120 | 0.330 | 285 | 0.072 |
135 | 0.287 | 300 | 0.063 |
150 | 0.250 |
*Day of calibration | |||||
TABLE 2 Sr-85/Sr-82 Ratio Chart (Sr-85 T ½ = 65 days, Sr-82 ½ = 25 days) |
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0* | 1.00 | 16 | 1.31 | 32 | 1.73 |
1 | 1.02 | 17 | 1.34 | 33 | 1.76 |
2 | 1.03 | 18 | 1.36 | 34 | 1.79 |
3 | 1.05 | 19 | 1.38 | 35 | 1.82 |
4 | 1.07 | 20 | 1.41 | 36 | 1.85 |
5 | 1.09 | 21 | 1.43 | 37 | 1.88 |
6 | 1.11 | 22 | 1.46 | 38 | 1.91 |
7 | 1.13 | 23 | 1.48 | 39 | 1.95 |
8 | 1.15 | 24 | 1.51 | 40 | 1.98 |
9 | 1.17 | 25 | 1.53 | 41 | 2.01 |
10 | 1.19 | 26 | 1.56 | 42 | 2.05 |
11 | 1.21 | 27 | 1.58 | ||
12 | 1.23 | 28 | 1.61 | ||
13 | 1.25 | 29 | 1.64 | ||
14 | 1.27 | 30 | 1.67 | ||
15 | 1.29 | 31 | 1.70 |
Stop use of the CardioGen-82 generator once any one of the following Expiration Limits is reached.
The estimated absorbed radiation doses for Rb-82, Sr-82, and Sr-85 from an intravenous injection rubidium Rb- 82 chloride are shown in Table 3.
Organa,b | Rb-82
(Average for Rest and Stress) mrem/mCi (µSv/3.7 MBq)c | Sr-82
mrem/µCi (µSv/3.7kBq)c | Sr-85
mrem/µCi (µSv/3.7kBq)c |
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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 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 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 |
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Adrenals | 7.56 | 10.6 | 5.03 |
Bone – Osteogenic cells
Bone Surface | 1.86
---- | ---
107 | ---
9.81 |
Brain | 0.60 | 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 | 2.50 |
Liver | 4.20 | 8.10 | 2.50 |
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 | 9.10 | 3.46 |
Red Marrow | 1.19 | 91.0 | 9.84 |
Skin | 1.14 | 7.03 | 1.75 |
Small Intestine | 4.76 | 9.62 | 4.03 |
Spleen | 6.61 | 8.10 | 2.54 |
Stomach | 8.14 | 7.84 | 2.26 |
Testes | 0.82 | 7.25 | 1.70 |
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 | 2.90 |
Uterus | 3.72 | 9.14 | 3.32 |
Total Body | 1.77 | Not Calculated | Not Calculated |
Effective Dosee | .74f4 | 23.4 | 4.03 |
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 90-150 millicuries Sr-82 at calibration time.
Unintended radiation exposure occurs when the Sr-82 and Sr-85 levels in rubidium Rb 82 chloride injections exceed the specified generator eluate limits. Unintended exposure to strontium radiation has occurred in some patients who received rubidium Rb 82 injections at clinical sites where generator eluate testing appeared insufficient. The physical half lives of Sr-82 and Sr-85 are 25 days and 65 days, respectively, in contrast to Rb-82 which has a physical half-life of 75 seconds. Unintended exposure to strontium radiation contributes to a patient’s overall cumulative radiation dose [see Warnings and Precautions (5.4)].
To minimize the risk of unintended radiation exposure, strict adherence to a daily eluate testing protocol is required. 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.
Unintended 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 (5.1), and Dosage and Administration (2.5)].
Animal reproductive studies have not been conducted with rubidium Rb 82 chloride injection. It is also not known whether rubidium Rb 82 chloride injection can cause fetal harm when administered to a pregnant woman; 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. Administer rubidium Rb-82 to a pregnant woman only if clearly needed.
It is not known whether rubidium Rb 82 chloride injection is excreted in human milk. Due to the short half-life of rubidium Rb-82 (75 seconds) it is unlikely that the drug would be excreted in human milk during lactation. However, because many drugs are excreted in human milk, caution should be exercised when rubidium Rb-82 chloride injection is administered to nursing women. Do not resume breastfeeding until one hour after the last 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 (2.2)]. Observe for the possibility of fluid overload [see Warnings and Precautions (5.3)].
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 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
TABLE
4 Principal Radiation Emission Data |
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Radiation | Mean Percent Per Disintegration | Mean Energy (keV) |
Annihilation photons (2) | 191.01 | 511 (each) |
Gamma rays | 13-15 | 776.5 |
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.
TABLE
5 Radiation Attenuation by Lead Shielding |
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Shield Thickness (Pb) cm | Attenuation Factor |
0.7 | 0.5 |
2.3 | 10 -1 |
4.7 | 10-2 |
7.0 | 10-3 |
9.3 | 10-4 |
Sr-82 (half-life of 25 days (600 hrs)) decays to Rb-82. To correct for physical decay of Sr-82, Table 6 shows the fractions that remain at selected intervals after the time of calibration.
*Calibration time | |||||
TABLE
6 Physical Decay Chart: Sr-82 half-life 25 days |
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Days | Fraction Remaining | Days | Fraction Remaining | Days | Fraction Remaining |
0* | 1.000 | 15 | 0.660 | 30 | 0.435 |
1 | 0.973 | 16 | 0.642 | 31 | 0.423 |
2 | 0.946 | 17 | 0.624 | 32 | 0.412 |
3 | 0.920 | 18 | 0.607 | 33 | 0.401 |
4 | 0.895 | 19 | 0.591 | 34 | 0.390 |
5 | 0.871 | 20 | 0.574 | 35 | 0.379 |
6 | 0.847 | 21 | 0.559 | 36 | 0.369 |
7 | 0.824 | 22 | 0.543 | 37 | 0.359 |
8 | 0.801 | 23 | 0.529 | 38 | 0.349 |
9 | 0.779 | 24 | 0.514 | 39 | 0.339 |
10 | 0.758 | 25 | 0.500 | 40 | 0.330 |
11 | 0.737 | 26 | 0.486 | 41 | 0.321 |
12 | 0.717 | 27 | 0.473 | 42 | 0.312 |
13 | 0.697 | 28 | 0.460 | ||
14 | 0.678 | 29 | 0.448 |
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.
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 (2.2)].
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.
Patients should be advised to inform their physician or healthcare provider if they are pregnant or breast feeding.
CARDIOGEN-82
rubidium chloride rb-82 injection, solution |
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Labeler - BRACCO DIAGNOSTICS INC. (849234661) |
Registrant - BRACCO DIAGNOSTICS INC. (849234661) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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Nordion (Canada) Inc | 201112088 | API MANUFACTURE |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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GE HEALTHCARE INC. | 154129886 | MANUFACTURE |