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Black Box Warning
WARNING: UNINTENDED STRONTIUM-82 (SR-82) AND STRONTIUM-85 (SR-85) RADIATION EXPOSURE:
See full prescribing information for complete Boxed Warning.
UNINTENDED STRONTIUM-82 (SR-82) AND STRONTIUM-85 (SR-85) RADIATION EXPOSURE:
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:
Record each generator eluate volume, including waste and test volumes, and keep a record of the cumulative eluate volume [see Dosage and Administration (2.4)].
Determine Rb-82, Sr-82, Sr-85 in the generator eluate:
●Once a day, prior to any drug administrations, and
●At additional daily tests after detection of an Alert Limit. Alert Limits are:
○14 L for the generator’s cumulative eluate volume, or
○An eluate Sr-82 level of 0.002 μCi/ mCi Rb-82, or
○An eluate Sr-85 level of 0.02 Sr-85 μCi/ mCi Rb-82.
○Perform the additional daily tests at time points determined by the day’s elution volume; tests are performed every 750 mL [see Dosage and Administration (2.5)].
Stop use of a generator at an Expiration Limit of:
○17 L for the generator’s cumulative eluate volume, or
○42 days post generator calibration date, or
○An eluate Sr-82 level of 0.01 μCi /mCi Rb-82, or
○An eluate Sr-85 level of 0.1 μCi /mCi Rb-82
Overview
Rubidium Rb 82 is a Diagnostic Agent that is FDA approved for the diagnosis of coronary artery disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Unintended radiation exposure.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
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.
Dosage
Infusion System
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).
2.2 Rubidium Rb 82 Chloride Injection Dosage
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).
Do not exceed a single dose of 2220 MBq (60 mCi).
Use the lowest dose necessary to obtain adequate cardiac visualization consistent with the dosing goal of as low as reasonably achievable (ALARA).
Individualize the dose by considering factors such as body size, and the imaging equipment and technique.
Administer the single dose at 50 mL/minute through a catheter inserted into a large peripheral vein; do not to exceed a total infusion volume of 100 mL.
Administer two separate single doses to complete rest and stress myocardial perfusion imaging as follows:
Administer a single (“rest”) rubidium Rb-82 chloride dose;
Start imaging 60-90 seconds after completion of the infusion of the rest dose and acquire images for 5 minutes; if a longer circulation time is anticipated (e.g., in a patient with severe left ventricular dysfunction), start imaging 120 seconds after the rest dose.
For stress imaging:
Begin the study 10 minutes after completion of the resting dose infusion, to allow for sufficient Rb-82 decay;
Administer a pharmacologic stress agent in accordance with its prescribing information;
After an interval of 3 minutes, infuse a single (“stress”) rubidium Rb-82 chloride dose;
Start imaging 60-90 seconds after completion of the stress Rb-82 chloride dose infusion and acquire images for 5 minutes; if a longer circulation time is anticipated start imaging 120 sec after the stress dose.
2.3 Drug Handling
Limit the use of radiopharmaceuticals to physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.
Wear waterproof gloves and effective shielding when handling rubidium Rb-82 chloride injection and the infusion system.
Observe aseptic techniques in all drug handling.
Use only additive-free Sodium Chloride Injection USP to elute the generator.
Visually inspect the drug for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer eluate from the generator if there is any evidence of foreign matter.
2.4 Directions for Eluting Rubidium Rb 82 Chloride Injection
Allow at least 10 minutes between elutions for regeneration of Rb-82.
Elute with additive-free Sodium Chloride Injection USP only. Additives (particularly calcium ions, to which strontium ions are chemically analogous), may cause the release of substantial amounts of Sr-82 and/or Sr-85 into the eluate regardless of the age or prior use of the generator.
Discard the first 50 mL eluate each day the generator is first eluted. Employ proper safety precautions since the eluate contains radioactivity.
Maintain an on-going record of all eluate volumes (washing, testing, dosing volumes), including a summary of the cumulative volume of eluate from the generator.
2.5 Eluate Testing Protocol
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:
Use an ionization chamber-type dose calibrator for eluate testing.
Daily, before administering rubidium Rb 82 chloride injection to any patient, perform an eluate testing to determine Rb-82, Sr-82, and Sr-85 levels
Perform additional daily eluate tests after detecting any of the following Alert Limits:
14 L total elution volume has passed through the generator column, or
Sr-82 level reaches 0.002 µCi per mCi Rb-82, or
Sr-85 level reaches 0.02 µCi per mCi Rb-82.
Perform the additional daily eluate tests at time points determined by the day’s elution volume; tests are performed every 750 mL.
For example, if an Alert Limit were reached and the clinical site eluted less than 750 mL from the generator during the day, then no additional eluate tests would have been performed that day.
If the same clinical site the next day eluted 1,500 mL from the generator, then the site would have performed three tests that day: 1) the required daily test that precedes any patient dosing, 2) a test at the 750 mL elution point, and 3) a test at the 1,500 mL elution point.
If a generator’s Alert Limit is reached, the clinical site performs the additional daily tests (at intervals of 750 mL) each subsequent day the generator is used. The additional tests are necessary to promptly detect excessive Sr-82 and/or Sr-85 in eluates.
Rubidium Eluate Level Testing:
Set a dose calibrator for Rb-82 as recommended by the manufacturer or use the Co-60 setting and divide the reading obtained by 0.548. Obtain the reading from the instrument in millicuries.
Elute the generator with 50 mL of Sodium Chloride Injection USP and discard the eluate (first elution).
Allow at least 10 minutes for the regeneration of Rb-82, then elute the generator with 50 mL of Sodium Chloride Injection USP at a rate of 50 mL/min and collect the eluate in a stoppered glass vial (plastic containers are not suitable). Note the exact time of end of elution (E.O.E.).
Using the dose calibrator, determine the activity of Rb-82 and note the time of the reading. Correct the reading for decay to the E.O.E. using the appropriate decay factor for Rb-82 (see Table 1).
Note: If the reading is taken 2 1/2 minutes after end of elution, multiply the dose calibrator reading by 4 to correct for decay.
Strontium Eluate Level Testing:
Using the sample obtained for the Rb-82 activity determination, allow the sample to stand for at least one hour to allow for the complete decay of Rb-82.
Measure the activity of the sample in a dose calibrator at the setting recommended by the manufacturer for Rb-82 and/or Sr-82. As an alternative, use the Co-60 setting and the reading obtained divided by 0.548. Set the instrument to read in microcuries and record the reading in the display.
Calculate the ratio (R) of Sr-85/Sr-82 on the day (post-calibration) of the measurement using the ratio of Sr-85/Sr-82 on the day of calibration provided on the generator label and the Sr-85/Sr-82 Ratio Factor from Table 2. Determine R using the following equation:
R = [Sr-85] / [Sr-82] on calibration date X Ratio Factor on the day (post-calibration) of measurement
Use a correction factor (F) of 0.478 to compensate for the contribution of Sr-85 to the reading.
Calculate the amount of Sr-82 in the sample using the following equation:
Sr-82 (μCi) = dose calibration reading (μCi) / [1 + (R) (F)]Example: dose calibrator reading (μCi) = 0.8; Sr85/Sr82 ratio (R) =1.48; correction factor (F) = 0.478.Sr-82 (μCi) = 0.8 / [1 + (1.48)(0.478)] = 0.47
Determine if Sr-82 in the eluate exceeds an Alert or Expiration Limit by dividing the μCi of Sr-82 by the mCi of Rb-82 at End of Elution (see below for further instructions based on the Sr-82 level)
Example: 0.47 μCi of Sr-82; 50 mCi of Rb-82 E.O.E.
0.47 μCi Sr-82 / 50 mCi Rb-82 = 0.0094 μCi/mCi Rb-82 (is above Alert Limit of 0.002; additional daily eluate testing must be performed)
Determine if Sr-85 in the eluate exceeds an Alert or Expiration Limit by multiplying the result obtained in step 10 by (R) as calculated in step 7 (above).
Example: 0.0094 x 1.48 = 0.014 μCi Sr-85/mCi Rb-82 (test result is below Alert and Expiration Limits)
2.6 CardioGen-82 Expiration
Stop use of the CardioGen-82 generator once any one of the following Expiration Limits is reached.
A total elution volume of 17 L has passed through the generator column, or
42 days post calibration date, or
An eluate Sr-82 level of 0.01 μCi /mCi Rb-82, or
An eluate Sr-85 level of 0.1 μCi /mCi Rb-82.
2.7 Radiation Dosimetry
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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rubidium Rb 82 in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rubidium Rb 82 in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
safety and effectiveness not established in pediatric patients
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rubidium Rb 82 in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rubidium Rb 82 in pediatric patients.
Contraindications
None
Warnings
WARNING: UNINTENDED STRONTIUM-82 (SR-82) AND STRONTIUM-85 (SR-85) RADIATION EXPOSURE:
See full prescribing information for complete Boxed Warning.
UNINTENDED STRONTIUM-82 (SR-82) AND STRONTIUM-85 (SR-85) RADIATION EXPOSURE:
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:
Record each generator eluate volume, including waste and test volumes, and keep a record of the cumulative eluate volume [see Dosage and Administration (2.4)].
Determine Rb-82, Sr-82, Sr-85 in the generator eluate:
●Once a day, prior to any drug administrations, and
●At additional daily tests after detection of an Alert Limit. Alert Limits are:
○14 L for the generator’s cumulative eluate volume, or
○An eluate Sr-82 level of 0.002 μCi/ mCi Rb-82, or
○An eluate Sr-85 level of 0.02 Sr-85 μCi/ mCi Rb-82.
○Perform the additional daily tests at time points determined by the day’s elution volume; tests are performed every 750 mL [see Dosage and Administration (2.5)].
Stop use of a generator at an Expiration Limit of:
○17 L for the generator’s cumulative eluate volume, or
○42 days post generator calibration date, or
○An eluate Sr-82 level of 0.01 μCi /mCi Rb-82, or
○An eluate Sr-85 level of 0.1 μCi /mCi Rb-82
Unintended Sr-82 and Sr-85 Exposure
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)].
5.2 Risks Associated with Pharmacologic Stress
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.
5.3 Volume Overload
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.
5.4 Cumulative Radiation Exposure: Long-Term Risk of Cancer
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.
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Rubidium Rb 82 in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
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
Drug Interactions
Specific drug-drug interactions have not been studied.
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.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rubidium Rb 82 in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Rubidium Rb 82 during labor and delivery.
Nursing Mothers
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.
Pediatric Use
Rubidium Rb 82 chloride injection safety and effectiveness in pediatric patients have not been established.
Geriatic Use
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
Gender
There is no FDA guidance on the use of Rubidium Rb 82 with respect to specific gender populations.
Race
There is no FDA guidance on the use of Rubidium Rb 82 with respect to specific racial populations.
Renal Impairment
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.
Hepatic Impairment
Reductions in hepatic function are not anticipated to alter clearance of rubidium Rb 82 chloride injection.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rubidium Rb 82 in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Rubidium Rb 82 in patients who are immunocompromised.
Administration and Monitoring
Administration
Intravenous
Monitoring
There is limited information regarding Monitoring of Rubidium Rb 82 in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Rubidium Rb 82 in the drug label.
Overdosage
There is limited information regarding Overdose of Rubidium Rb 82 in the drug label.
Pharmacology
There is limited information regarding Rubidium Rb 82 Pharmacology in the drug label.
