Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action 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. Pharmacodynamics 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. Pharmacokinetics 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. Clinical Studies 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.

CLINICAL PHARMACOLOGY Mechanism of Action 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. Pharmacodynamics 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]. 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. Pharmacokinetics 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. Clinical Studies 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. REFERENCES 6. Demer, L.L. et al. Assessment of coronary artery disease severity by PET: Comparison with quantitative arteriography in 193 patients. Circulation 1989; 79: 825-35.

RUBY-FILL (rubidium Rb 82) Generator 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]. Perform generator eluate tests: The system automatically generates a record and saves the data for each generator eluate volume, including flushing and test volumes. Total cumulative eluate volumes are also recorded and saved for the life of the generator [see DOSAGE AND ADMINISTRATION]. Determine Rb 82, Sr 82, Sr 85 in the generator eluate: Once a day, prior to any drug administration, and At additional daily tests after detection of an Alert Limit. Alert Limits are: 20 L for the generator's cumulative eluate volume, or An eluate Sr 82 level of 0.004 μCi/ mCi (kBq/MBq) Rb 82, or An eluate Sr 85 level of 0.04 μCi/ mCi (kBq/MBq) Rb 82. Perform additional daily tests every 4 patients after detection of an alert limit [see DOSAGE AND ADMINISTRATION]. Stop use of a generator at any of the following Expiration Limits. Expiry Limits are: 30 L for the generator's cumulative eluate volume, or Expiration date of the generator (60 days post-manufacturing) An eluate Sr 82 level of 0.01 μCi /mCi (kBq/MBq) Rb 82, or An eluate Sr 85 level of 0.1 μCi /mCi (kBq/MBq) Rb 82 [see DOSAGE AND ADMINISTRATION]. DESCRIPTION Chemical Characteristics 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 370-2220 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. Physical Characteristics 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 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 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 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].

CARDIOGEN-82 ® (rubidium Rb 82 generator) 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] Perform generator eluate tests: 1) Record each generator eluate volume, including waste and test volumes, and keep a record of the cumulative eluate volume [see DOSAGE AND ADMINISTRATION]. 2) 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]. 3) 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 [see DOSAGE AND ADMINISTRATION]. DESCRIPTION Chemical Characteristics 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. Physical Characteristics 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 Radiation Mean Percent Per Disintegration Mean Energy (keV) Annihilation photons (2) 191.01 511 (each) Gamma rays 13-15 776.5 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 10-13Sv/Bq . dCalculated from ICRP 66 eCalculated from ICRP 60 fStress phase only 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 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. TABLE 6 : Physical Decay Chart: Sr-82 half-life 25 days 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 *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]. REFERENCES 1.  Senthamizhchelvan S. et al. Human biodistribution and radiation dosimetry of 82Rb. J Nucl Med, 2010; 51:1592 – 99. 2. Senthamizhchelvan S. et al. Radiation dosimetry of 82Rb in humans under pharmacologic stress. J Nucl Med 2011; 52: 485-91 3. Eckerman, K. F. et al. User's Guide to the DCAL System, ORNL/TM-2001-190; Oak Ridge National Laboratory, Oak Ridge, TN, August, 2006. 4. Lederer, M and Shirley, V. Table of Isotopes, 7th Edition. 5. Judge, S et al. Applied radiation and isotopes (1987); vol 38, no. 3: pp 185-90.

INDICATIONS 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. DOSAGE AND ADMINISTRATION Radiation Safety -Drug Handling 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]). Use waterproof gloves and effective shielding when handling rubidium Rb 82 chloride injection and the RUBY Rubidium Elution System. Use aseptic techniques in all drug handling. 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. Recommended Dose And Administration Instructions The recommended weight-based dose of rubidium Rb 82 chloride to be administered per rest or stress component of a PET myocardial perfusion imaging (MPI) procedure is between 10-30 Megabecquerels (MBq)/kg [0.27-0.81 millicuries (mCi)/kg]. Do not exceed a single dose of 2220 MBq (60 mCi). Use the lowest dose necessary to obtain adequate cardiac visualization and individualize the weight-based dose depending on multiple factors, including, patient weight, imaging equipment and acquisition type used to perform the procedure. For example, 3D imaging acquisition may require doses at the lower end of the recommended range compared to 2D imaging. Administer the single dose at a rate of 15 -30 mL/minute through a catheter inserted into a large peripheral vein; do not exceed an infusion volume of 60 mL. Instruct patients to void as soon as a study is completed and as often as possible thereafter for at least one hour. The maximum available activity (delivery limit) will decrease as the generator ages [see RUBY-FILL Dose Delivery Limit]. Image Acquisition Guidelines For Rest Imaging: 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 3-7 minutes. 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 administration of the pharmacologic stress agent, administer the second dose of Rb 82 at the time interval according to the prescribing information of the pharmacological stress agent; Start imaging 60-90 seconds after completion of the stress rubidium Rb 82 chloride dose infusion and acquire images for 3-7 minutes. For Both Rest and Stress Imaging: 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. Acquisition may be started immediately post-injection if dynamic imaging is needed. Elution System Use RUBY-FILL Rubidium Rb 82 Generator only with an elution system specifically designed for use with the generator (RUBY Rubidium Elution System) and capable of accurate measurement and delivery of doses of rubidium Rb 82 chloride injection. The generator used with the elution system provides ± 10% accuracy for rubidium Rb 82 chloride doses between 370-2220 MBq (10-60 mCi) Follow instructions in the RUBY Rubidium Elution System User Manual for the set up and intravenous infusion of rubidium Rb 82 chloride injection dose. Directions For Eluting Rubidium Rb 82 Chloride Injection Allow at least 10 minutes between elutions for regeneration of Rb 82. Elute with additive-free 0.9% 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. The system will automatically discard the first 75 mL eluate each day the generator is first eluted. The RUBY Rubidium Elution System automatically generates records and saves data of all eluate volumes (from flushing, QC testing, patient infusions), representing the cumulative volume of eluate from the generator. Eluate Testing Protocol Elute with additive-free 0.9% Sodium Chloride Injection USP only. Use the ionization chamber-type dose calibrator that is integrated into the elution system (used specifically with the RUBYFILL Rubidium Rb 82 Generator) for eluate testing. Perform Mandatory Eluate Testing (i.e. Quality Control test) to determine Rb 82, Sr 82, and Sr 85 levels: Daily -Before administering rubidium Rb 82 chloride injection to the first patient each day. Repeat Every 4 patients after an Alert Limit has been detected. Alert Limits: 20 L total elution volume has passed through the generator column, or Sr 82 level reaches 0.004 μCi per mCi (kBq per MBq) Rb 82, or Sr 85 level reaches 0.04 μCi per mCi (kBq per MBq) Rb 82. 3. Immediately after detection of the volume alert limit (20 L). The elution system will automatically indicate when alert limits have been reached and require that additional tests be performed. When the Quality Control test is performed as described in the User Manual, the system automatically performs the following eluate testing: Rubidium Eluate Testing: The dose calibrator is automatically set for Rb 82 within the Elution System. The Quality Control test begins by automatically initiating a generator flush using 75 mL of 0.9% Sodium Chloride Injection USP. This eluate is by default diverted towards the waste container and is ultimately discarded. After the generator flush, the system waits approximately 15.2 minutes to accomplish a complete generator recharge of 12 Rb 82 half-lives The system then elutes a calibration sample (35 mL of 0.9% Sodium Chloride Injection USP at 20 mL/min). Using the dose calibrator, the system automatically quantifies the activity of Rb 82 in the calibration sample (Rb 82 decay does not need to be corrected for because of a real-time automated measurement). Strontium Eluate Testing (Strontium Breakthrough): Using the calibration sample obtained from the Rb 82 eluate testing, the system allows the sample to stand for 30 minutes to allow for the complete decay of Rb 82. The system measures the activity of the sample to automatically determine the total Sr 82 and Sr 85 activity. The system automatically determines the ratio (R) 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 the Sr 85/Sr 82 ratio based on generator age using the following equation: R = [Sr 85]/ [Sr 82] on calibration date X Ratio Factor on the day (post-calibration) of measurement The system uses a correction factor (F) of 0.48 to compensate for the contribution of Sr 85 to the reading. The system calculates the amount of Sr 82 in the sample using the following equation: In Empirical Units (μCi): Sr 82 (μCi) = dose calibration reading (μCi) [1 + (R) (F)] Example: dose calibrator reading (μCi) = 0.8 Sr 85/Sr 82 ratio (R) = (1.48) correction factor (F) = 0.48 Sr 82 (μCi) = 0.8 μCi = 0.47 μCi [1 + (1.48)(0.48)] In International Units (kBq) Sr 82 (kBq) = dose calibration reading (μCi) [1 + (R) (F)] Example: dose calibrator reading (kBq) = 29.6 kBq Sr 85/Sr 82 ratio (R) = (1.48) correction factor (F) = 0.48 Sr 82 (kBq) = 29.6 kBq = 17.3 kBq [1 + (1.48)(0.48)] 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) In Empirical Units (μCi) Example: 0.47 μCi of Sr 82; 50 mCi of Rb 82 0.47 μCi Sr 82 = = 0.0094 μCi Sr 82 50 mCi Rb 82 mCi Rb 82 (Sr 82 is above Alert Limit of 0.004 μCi/mCi; additional daily eluate testing must be performed) In International Units (kBq) Example: 17.3 kBq of Sr 82; 1850 MBq of Rb 82 17.3 kBq Sr 82 = 0.0094 kBq Sr 82 1850 MBq Rb 82 MBq Rb 82 (Sr 82 is above Alert Limit of 0.004 kBq/MBq; additional daily eluate testing must be performed) 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 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 *Elution time The system uses Table 2 to calculate the ratio (R) of Sr 85/Sr 82. TABLE 2 Sr 85/Sr 82 Ratio Chart (Sr 85 T½ = 65 days, Sr 82 T½ = 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 * Day of calibration. RUBY-FILL Expiration Stop use of the RUBY-FILL Rubidium Rb 82 Generator once any one of the following Expiration Limits is reached: A total elution volume of 30 L has passed through the generator column, or Expiration date of the generator (60 days post-manufacturing), or An eluate Sr 82 level of 0.01 μCi/mCi (kBq/MBq) Rb 82, or An eluate Sr 85 level of 0.1 μCi/mCi (kBq/MBq) Rb 82. RUBY-FILL Dose Delivery Limit 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. 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) 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. Radiation Dosimetry 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 82Rb1 (μGy/MBq) 82Sr2 (μGy/kBq) 85Sr2 (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 1.1μSv/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. HOW SUPPLIED Dosage Forms And Strengths 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. 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. Storage And Handling Store the generator at 20-25 °C (68-77 °F). Receipt, transfer, possession, storage, disposal or use of this product is subject to the radioactive material regulations and licensing requirements of the U.S. Nuclear Regulatory Commission (NRC), Agreement States or Licensing States as appropriate. Do not dispose of the generator in regular refuse systems. For questions about the disposal of the RUBY-FILL Rubidium Rb 82 Generator, contact Jubilant Draximage Inc. at 1-888633-5343. Manufactured by: Jubilant DRAXIMAGE Inc. 16751 TransCanada Highway Kirkland, Québec, Canada H9H 4J4. Revised: Sep 2016

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 AND ADMINISTRATION 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). 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: For rest imaging: 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. 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. 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. 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 1. 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. 2. Elute the generator with 50 mL of Sodium Chloride Injection USP and discard the eluate (first elution). 3. 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.). 4. 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 ½ minutes after end of elution, multiply the dose calibrator reading by 4 to correct for decay. Strontium Eluate Level Testing 5. 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. 6. 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. 7. Calculate the ratio (R) of Sr-85/Sr-82 on the day (postcalibration) of the measurement using the ratio of Sr85/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] on calibration date X Ratio Factor on the day (post-calibration) of measurement [Sr-82] 8. Use a correction factor (F) of 0.478 to compensate for the contribution of Sr-85 to the reading. 9. 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 = 0.47 [1 + (1.48)(0.478)] 10. 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 = 0.0094 μCi/mCi Rb-82 (is above Alert Limit of 0.002; additional daily eluate testing must be performed 50 mCi Rb-82 11. 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) Use Table 1 to calculate the decay factor for Rb-82; step 4 (above). TABLE 1 : Physical Decay Chart: Rb-82 half-life 75 seconds 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 *Elution time Use Table 2 to calculate the ratio (R) of Sr-85/Sr-82; step 7 (above). TABLE 2 : Sr-85/Sr-82 Ratio Chart (Sr-85 T ½= 65 days, Sr-82½= 25 days) Days Ratio Factor Days Ratio Factor Days Ratio Factor 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 *Day of calibration 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. 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. Table 3 : Adult Absorbed Radiation Dose Coefficient 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 Adrenals 7.56 10.6 5.03 Bone – Osteogenic cells 1.86 --- --- Bone Surface ---- 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 4.74 f 23.4 4.03 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 10-13Sv/Bq . dCalculated from ICRP 66 eCalculated from ICRP 60 fStress phase only HOW SUPPLIED Dosage Forms And Strengths 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. Storage And Handling 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]. 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. Disposal 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. Storage Store the generator at 20-25°C (68-77°F) [See USP]. Manufactured for Bracco Diagnostics Inc. Princeton, NJ 08543 by Medi-Physics, Inc., South Plainfield, NJ 07080. Revised: 2/2012

PATIENT INFORMATION 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.

PATIENT INFORMATION Women of Childbearing Potential Patients should be advised to inform their physician or healthcare provider if they are pregnant or breast-feeding. Post-study Breastfeeding Avoidance Instruct nursing patients to substitute stored breast milk or infant formula for breast milk for one hour after administration of rubidium Rb 82 chloride injection. Post-study Voiding 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.

OVERDOSE No information provided. CONTRAINDICATIONS None.

SIDE EFFECTS 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, DOSAGE AND ADMINISTRATION]. DRUG INTERACTIONS No information provided.

SIDE EFFECTS 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 [see BOXED WARNING, WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION]. DRUG INTERACTIONS Specific drug-drug interactions have not been studied.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Unintended Sr 82 And Sr 85 Radiation 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. 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]. 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. Radiation Risks 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]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility 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. Use In Specific Populations Pregnancy 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 1520%, respectively. Lactation 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. Pediatric Use The safety and effectiveness of rubidium Rb 82 chloride injection in pediatric patients have not been established. Geriatric Use In elderly patients with a clinically important decrease in cardiac function, lengthen the delay between infusion and image acquisition [see DOSAGE AND ADMINISTRATION]. Observe for the possibility of fluid overload from the infusion.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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. 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]. 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. 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. 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]. Encourage patients to void as soon as a study is completed and as often as possible thereafter for at least one hour. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility 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. Use In Specific Populations Pregnancy Pregnancy Category C 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. 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. Geriatric Use In elderly patients with a clinically important decrease in cardiac function, lengthen the delay between infusion and image acquisition [see DOSAGE AND ADMINISTRATION]. Observe for the possibility of fluid overload [see WARNINGS AND PRECAUTIONS]. 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.