RUBY-FILL- rubidium rb 82 injection, solution
Jubilant DraxImage Inc., dba Jubilant Radiopharma
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use RUBY-FILL safely and effectively. See full prescribing information for RUBY-FILL.
RUBY-FILL (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 QUALITY CONTROL TESTING PROCEDURE
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High Level Radiation Exposure with Use of Incorrect Eluent
Patients are exposed to high radiation levels when the generator is eluted with the incorrect eluent due to high Sr 82 and Sr 85 breakthrough levels [see Warnings and Precautions (5.1)]
Excess Radiation Exposure with Failure to Follow Quality Control Testing Procedure
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)].
RUBY-FILL 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 (5.3]).
For Rest Imaging:
For Stress Imaging:
For Both Rest and Stress Imaging:
When the Quality Control Testing Procedure is performed as described in the User Manual, the system automatically performs the following eluate testing:
Rubidium Eluate Testing:
Strontium Eluate Testing (Strontium Breakthrough):
4. The system uses a correction factor (F) of 0.48 to compensate for the contribution of Sr 85 to the reading.
5. The system calculates the amount of Sr 82 in the sample using the following equation:
6. The system determines if Sr 82 in the eluate exceeds an Alert or Expiration Limit by dividing the mcCi (or kBq) of Sr 82 by the mCi (or MBq) of Rb 82 at End of Elution (see below for further instructions based on the Sr 82 level)
7. The system determines if Sr 85 in the eluate exceeds an Alert or Expiration Limit by multiplying the result obtained in step 6 by (R) as calculated in step 3 (above).
The system uses Table 1 to calculate the decay factor for Rb 82
TABLE 1 |
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Physical Decay Chart: Rb 82 half-life 75 seconds |
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Seconds |
Fraction Remaining |
Seconds |
Fraction Remaining |
0* |
1.00 |
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 |
*Elution time
The system uses Table 2 to calculate the ratio (R) of Sr 85/Sr 82.
Sr 85/Sr 82 Ratio Chart (Sr 85 T1/2 = 65 days, Sr 82 T1/2 = 25 days) |
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Days | RatioFactor | Days | Ratio Factor | Days | Ratio Factor |
0* |
1.00 |
21 |
1.43 |
42 |
2.05 |
1 |
1.02 |
22 |
1.46 |
43 |
2.08 |
2 |
1.03 |
23 |
1.48 |
44 |
2.12 |
3 |
1.05 |
24 |
1.51 |
45 |
2.15 |
4 |
1.07 |
25 |
1.53 |
46 |
2.19 |
5 |
1.09 |
26 |
1.56 |
47 |
2.23 |
6 |
1.11 |
27 |
1.58 |
48 |
2.27 |
7 |
1.13 |
28 |
1.61 |
49 |
2.30 |
8 |
1.15 |
29 |
1.64 |
50 |
2.34 |
9 |
1.17 |
30 |
1.67 |
51 |
2.38 |
10 |
1.19 |
31 |
1.70 |
52 |
2.43 |
11 |
1.21 |
32 |
1.73 |
53 |
2.47 |
12 |
1.23 |
33 |
1.76 |
54 |
2.51 |
13 |
1.25 |
34 |
1.79 |
55 |
2.55 |
14 |
1.27 |
35 |
1.82 |
56 |
2.60 |
15 |
1.29 |
36 |
1.85 |
57 |
2.64 |
16 |
1.31 |
37 |
1.88 |
58 |
2.69 |
17 |
1.34 |
38 |
1.91 |
59 |
2.73 |
18 |
1.36 |
39 |
1.95 |
60 |
2.78 |
19 |
1.38 |
40 |
1.98 | ||
20 |
1.41 |
41 |
2.01 |
* Day of Calibration.
Stop use of the RUBY-FILL Rubidium Rb 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 (2220 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.
Generator Age (days) 2 |
Maximum Rubidium Dose (Delivery Limit) |
0 to 17 |
60 mCi (2220 MBq) |
24 |
50 mCi (1850 MBq) |
32 |
40 mCi (1480 MBq) |
42 |
30 mCi (1110 MBq) |
57 |
20 mCi ( 740 MBq) |
1Estimate is based on a 100 mCi (3700 MBq) Sr 82 generator at calibration.
2Generator age at which delivery limit is reached varies with generator activity at release. For example, an 85 mCi (3145 MBq) generator and a 115 mCi (4255 MBq) generator will reach a delivery limit < 60 mCi at ≥ 12 days and ≥ 23 days, respectively.
The estimated radiation absorbed dose coefficients for Rb 82, Sr 82, and Sr 85 from an intravenous injection of rubidium Rb 82 chloride are shown in Table 4.
TABLE 4
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Organ |
82Rb1 (mcGy/MBq) |
82Sr2 (mcGy/kBq) |
85Sr2 (mcGy/kBq) |
Adrenals |
2.4 |
2.9 |
1.4 |
Bone surfaces |
0.42 |
29 |
2.7 |
Brain |
0.14 |
2.2 |
0.8 |
Breast |
0.19 |
1.9 |
0.5 |
Gallbladder wall |
0.72 |
2.3 |
0.8 |
Gastrointestinal tract | |||
Esophagus3 |
1.5 |
2.1 |
0.6 |
Stomach wall |
0.83 |
2.1 |
0.6 |
Small intestine wall |
2.0 |
2.6 |
1.1 |
Colon wall |
1.1 |
9.7 |
1.2 |
(ULI wall) |
1.1 |
6.4 |
1.0 |
(LLI wall) |
1.1 |
14 |
1.4 |
Heart wall |
4.0 |
2.2 |
0.7 |
Kidneys |
9.3 |
2.5 |
0.7 |
Liver |
1.0 |
2.2 |
0.7 |
Lungs |
2.6 |
2.2 |
0.8 |
Muscles |
0.23 |
2.2 |
0.7 |
Ovaries |
0.50 |
2.8 |
1.2 |
Pancreas |
2.6 |
2.5 |
0.9 |
Red marrow |
0.38 |
25 |
2.7 |
Skin |
0.18 |
1.9 |
0.5 |
Spleen |
0.18 |
2.2 |
0.7 |
Testes |
0.26 |
2.0 |
0.5 |
Thymus |
1.5 |
2.1 |
0.6 |
Thyroid |
0.31 |
2.2 |
0.7 |
Urinary bladder wall |
0.18 |
5.9 |
0.8 |
Uterus |
1.0 |
2.5 |
0.9 |
Remaining organs |
0.31 |
- |
- |
Effective dose per unit activity |
1.1 mcSv/MBq |
6.3 mcSv/kBq |
1.1 mcSv/kBq |
1 Rb 82 doses are averages of rest and stress dosimetry data. To calculate organ doses (mcGy) from Rb 82, multiply the dose coefficient for each organ by the administered activity in MBq. 2 To calculate organ doses attributable to Sr 82 and Sr 85, multiply those dose coefficients by the respective strontium activities associated with the injection. 3The absorbed dose to the thymus is used as a substitute. |
RUBY-FILL is a closed system used to produce rubidium Rb 82 chloride injection for intravenous use. RUBY-FILL consists of Sr 82 adsorbed on a hydrous stannic oxide column with an activity of 3145 to 4255 MBq (85 to 115 mCi) Sr 82 at calibration time.
RUBY-FILL is contraindicated for use 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 RUBY-FILL generator whenever the incorrect eluent is used [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.1)].
Use only additive-free 0.9% Sodium Chloride Injection USP to elute the generator. Apply the provided saline confirmation label to the additive-free 0.9% Sodium Chloride Injection USP bag 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, 2.6)].
Immediately stop the patient infusion and discontinue use of the affected RUBY-FILL 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 the eluate, even with the subsequent use of additive-free 0.9% Sodium Chloride Injection USP [see Boxed Warning, Dosage and Administration (2.9), 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 quality control testing procedure to minimize radiation exposure to the patient. Stop using the rubidium generator when the expiration limits are reached [see Dosage and Administration (2.6) and (2.7)].
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.
RUBY-FILL use contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Ensure safe handling to minimize radiation exposure to the patient and health care providers. Encourage patients to void as soon as a study is completed and as often as possible thereafter for at least one hour [see Dosage and Administration (2.1) and (2.2)].
The following serious adverse reaction associated with the use of rubidium Rb 82 chloride was identified in clinical trials or post marketing reports. 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.
Radiation 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, Warnings and Precautions (5.1)]. Excess radiation exposure has occurred in some patients who received rubidium Rb 82 chloride injection at clinical sites where generator eluate testing appeared insufficient [see Boxed Warning, Warnings and Precautions (5.2), Dosage and Administration (2.6)].
Risk Summary
There are no data available on the use of rubidium Rb 82 in pregnant women. Animal reproduction studies with rubidium Rb 82 chloride have not been conducted. 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 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 to 4% and 15 to 20%, respectively.
Risk Summary
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 Rb 82 chloride (75 seconds), exposure of a breast fed 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, any potential adverse effects on the breastfed child from Rb 82 or from the underlying maternal condition.
Clinical Considerations
Minimizing Exposure
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 RUBY-FILL infusion.
The safety and effectiveness of rubidium Rb 82 chloride injection 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 from the infusion.
RUBY-FILL Rubidium Rb 82 Generator contains accelerator-produced Sr 82 adsorbed on stannic oxide in a lead-shielded column and provides a means for obtaining sterile non-pyrogenic solutions of rubidium Rb 82 chloride injection. The chemical form of Rb 82 is 82RbCl.
The amount (mCi) of Rb 82 obtained in each elution will depend on the potency of the generator. When used with the RUBY Rubidium Elution System, the generator provides ± 10% accuracy for rubidium Rb 82 chloride doses between 370 to 2220 MBq (10 to 60 mCi).
When eluted at a rate of 15 to 30 mL/minute, each generator eluate at the end of elution should not contain more than 0.02 mcCi (0.74 kBq) of Sr 82 and not more than 0.2 mcCi (7.4 kBq) of Sr 85 per mCi of rubidium Rb 82 chloride injection, and not more than 1 mcg of tin per mL of eluate.
Rb 82 decays by positron emission and associated gamma emission with a physical half-life of 75 seconds. 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.
TABLE 5
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 to 15 | 776.5 |
The specific gamma ray constant for Rb 82 is 6.33 R cm2 / mCi h (1.23 × 10-12 C m2 / kg MBq s). The first half-value layer is 0.53 cm 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 Pb. For example, the use of a 6.15 cm thickness of Pb will attenuate the radiation emitted by a factor of about 1,000.
TABLE 6
Radiation Attenuation by Lead Shielding |
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Shield Thickness (Pb) cm | Attenuation Factor |
0.53 | 0.5 |
1.68 | 10-1 |
3.55 | 10-2 |
6.15 | 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 7 shows the fractions that remain at selected intervals after the time of calibration.
TABLE 7
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 | 21 | 0.559 | 41 | 0.321 |
1 | 0.973 | 22 | 0.543 | 42 | 0.312 |
2 | 0.946 | 23 | 0.529 | 43 | 0.304 |
3 | 0.920 | 24 | 0.514 | 44 | 0.295 |
4 | 0.895 | 25 | 0.500 | 45 | 0.287 |
5 | 0.871 | 26 | 0.486 | 46 | 0.279 |
6 | 0.847 | 27 | 0.473 | 47 | 0.272 |
7 | 0.824 | 28 | 0.460 | 48 | 0.264 |
8 | 0.801 | 29 | 0.448 | 49 | 0.257 |
9 | 0.779 | 30 | 0.435 | 50 | 0.250 |
10 | 0.758 | 31 | 0.423 | 51 | 0.243 |
11 | 0.737 | 32 | 0.412 | 52 | 0.237 |
12 | 0.717 | 33 | 0.401 | 53 | 0.230 |
13 | 0.697 | 34 | 0.390 | 54 | 0.224 |
14 | 0.678 | 35 | 0.379 | 55 | 0.218 |
15 | 0.660 | 36 | 0.369 | 56 | 0.212 |
16 | 0.642 | 37 | 0.358 | 57 | 0.206 |
17 | 0.624 | 38 | 0.349 | 58 | 0.200 |
18 | 0.607 | 39 | 0.339 | 59 | 0.195 |
19 | 0.591 | 40 | 0.330 | 60 | 0.189 |
20 | 0.574 |
* Calibration time
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)].
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 in viable myocardium is higher than in infarcted tissue, reflecting intracellular retention.
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 to 7 minutes after injection as photon-deficient, or “cold”, areas on the myocardial perfusion scan. In patients with reduced cardiac function, transit of the injected dose from the peripheral infusion site to the myocardium may be delayed.
Blood flow brings Rb 82 to all areas of the body during the first pass of circulation. Accordingly, visible uptake is observed in highly vascularized organs, such as the kidneys, liver, spleen and lungs.
In a descriptive, prospective, blinded image interpretation study 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 Rb 82 (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.
RUBY-FILL Rubidium Rb 82 Generator consists of Sr 82 adsorbed on a hydrous stannic oxide column with an activity of 3145 to 4255 MBq (85 to 115 mCi) Sr 82 at calibration time. A lead shield encases the generator. The container label provides complete assay data for each generator. Use RUBY-FILL Rubidium Rb 82 Generator only with an appropriate, properly calibrated Elution System (RUBY Rubidium Elution System) labeled for use with the generator.
Pregnancy
Advise a pregnant woman of the potential risk to a fetus.
Lactation
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.
General Safety Precautions
Advise patients to void after completion of each image acquisition session and as often as possible for one hour after completion of the PET scan.
RUBY-FILL
rubidium rb 82 injection, solution |
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Labeler - Jubilant DraxImage Inc., dba Jubilant Radiopharma (243604761) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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Jubilant DraxImage Inc., dba Jubilant Radiopharma | 243604761 | MANUFACTURE(65174-021) |