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These 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 useInitial | RUBY-FILL [Jubilant DraxImage Inc.] | BioPortfolio

13:47 EST 27th January 2019 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

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:

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 test 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 μCi (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).

In Empirical Units (µCi)

Example: 0.0094 x 1.48 = 0.014 μCi Sr 85/mCi Rb 82

(Sr 85 test result is below Alert and Expiration Limits)

In International Units (kBq)

Example: 0.0094 x 1.48 = 0.014 kBq Sr 85/MBq Rb 82

(Sr 85 test result is below Alert and Expiration Limits)

The system uses Table 1 to calculate the decay factor for Rb 82

 *Elution time

The system uses Table 2 to calculate the ratio (R) of Sr 85/Sr 82.

* Day of Calibration.


TABLE 1

Physical Decay Chart: Rb 82 half-life 75 seconds

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

TABLE 2

Sr 85/Sr 82 Ratio Chart (Sr 85 T1/2 = 65 days, Sr 82 T1/2 = 25 days)

 Days

 Ratio Factor

 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

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.

Estimate is based on a 100 mCi (3700 MBq) Sr 82 generator at calibration. 

Generator 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.   

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 (2220 MBq)
   24 50 mCi (1850 MBq)
   32 40 mCi (1480 MBq)
   42 30 mCi (1110 MBq)
   57 20 mCi ( 740 MBq)

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
Adult absorbed dose per radioisotope activity associated with injection
Organ 82 Rb1 (µGy/MBq) 82 Sr2 (µGy/kBq) 85 Sr2 (µGy/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 µSv/MBq  6.3 µSv/kBq 1.1 µSv/kBq
1 Rb- 82 doses are averages of rest and stress dosimetry data. To calculate organ doses (µGy) 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 - 4255 MBq (85 - 115 mCi) Sr 82 at calibration time.

None.

Unintended radiation exposure occurs when the Sr 82 and Sr 85 levels in rubidium Rb 82 chloride injections exceed the specified generator eluate limits. 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 (2.6) 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.

Unintended Sr 82 and Sr 85 Radiation Exposure: Unintended 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 (5.1), 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 2-4% and 15-20%, 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 RbCl.

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 370-2220 MBq (10-60 mCi).

When eluted at a rate of 15 - 30 mL/minute, each generator eluate at the end of elution should not contain more than 0.02 µCi (0.74 kBq) of Sr 82 and not more than 0.2 µCi (7.4 kBq) of Sr 85 per mCi of rubidium Rb 82 chloride injection, and not more than 1 µg 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.

The specific gamma ray constant for Rb-82 is 6.33 R cm / mCi h (1.23 × 10 C m / 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.

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.

* 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)].

TABLE 5
Principal Radiation Emission Data

Radiation
Mean Percent
Per Disintegration
Mean Energy
(keV)
Annihilation photons (2) 191.01 511 (each)
Gamma rays 13 to 15 776.5
TABLE 6
Radiation Attenuation by Lead Shielding
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
TABLE 7
Physical Decay Chart: Sr-82 half-life 25 days
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

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 2-7 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.

With a physical half-life of 75 seconds, Rb 82 is converted by radioactive decay into stable Kr 82 gas, which is passively expired by the lungs.

No long-term studies have been performed to evaluate carcinogenic potential, mutagenicity potential, or to determine whether rubidium Rb 82 chloride injection may affect fertility in males or females.

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 – 4255 MBq (85 - 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.

Manufactured by:

Jubilant DRAXIMAGE Inc.16751 TransCanada HighwayKirkland, Québec, CanadaH9H 4J4

Version: 1

85 - 115 mCi

Generator column contains Strontium Sr 82 adsorbed on hydrous stannic oxide.

Store the generator at 20-25 ºC (68-77 ºF).

Rx only

Manufacturer

Jubilant DraxImage Inc. and Cyclopharm Limited

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