RUBY-FILL

1 INDICATIONS AND USAGE 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. RUBY-FILL is a closed system used to produce rubidium Rb 82 chloride injection for intravenous use. Rubidium Rb 82 chloride injection is a radioactive diagnostic agent 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. (1)

2 DOSAGE AND ADMINISTRATION Use RUBY-FILL with a specific Elution System. ( 2.4) • Use only additive-free 0.9% Sodium Chloride Injection USP to elute the generator. ( 2.5 ) • The recommended weight-based dose of rubidium Rb 82 is between 10 to 30 Megabecquerels (MBq)/kg [0.27 to 0.81 millicuries (mCi)/kg]. ( 2.2 ) • Do not exceed a single dose of 2220 MBq (60 mCi) per rest or stress component of a procedure. (2.2) • Administer the single dose at a rate of 15 to 30 mL/minute through a catheter inserted into a large peripheral vein; do not exceed an infusion volume of 60 mL. ( 2.2 ) • Use the lowest dose necessary to obtain adequate cardiac visualization and individualize the dose depending on multiple factors, including, patient weight, imaging equipment and acquisition type used to perform the procedure. ( 2.2 ) • Start imaging acquisition 60 to 90 seconds after completion of the infusion; if a longer circulation time is anticipated, wait for 120 seconds. Acquisition may be started immediately post-injection if dynamic imaging is needed. Image acquisition is typically 3 to 7 minutes long. ( 2.3 ) • To obtain rest and stress images, wait 10 minutes after completion of the rest image acquisition then administer the pharmacologic stress agent in accordance with its prescribing information. After administration of the pharmacologic stress agent, infuse the second dose of Rb 82, at the time interval according to the prescribing information of the pharmacological stress agent and complete the stress image acquisition. ( 2.3 ) 2.1 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 ( 5.3 ] ). Use only additive-free 0.9% Sodium Chloride Injection USP to elute the generator [ see Boxed Warning, Contraindications (4) , Warnings and Precautions ( 5.1 ) ]. 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. 2.2 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 to 30 Megabecquerels (MBq)/kg [0.27 to 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 to 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 Dosage and Administration ( 2.8 )] . 2.3 Image Acquisition Guidelines For Rest Imaging: Administer a single (“rest”) rubidium Rb 82 chloride dose; Start imaging 60 to 90 seconds after completion of the infusion of the rest dose and acquire images for 3 to 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 to 90 seconds after completion of the stress rubidium Rb 82 chloride dose infusion and acquire images for 3 to 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. 2.4 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 to 2220 MBq (10 to 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. 2.5 Directions for Eluting Rubidium Rb 82 Chloride Injection Use only additive-free 0.9 % Sodium Chloride Injection USP to elute the generator [see Boxed Warning, Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . Prepare the 0.9% Sodium Chloride Injection USP for use with the Saline Confirmation Label Affix the saline confirmation label provided with the RUBY Rubidium Elution System on the clear side of the additive-free 0.9% Sodium Chloride Injection USP bag and install on the RUBY Rubidium Elution System. Prepare the intravenous administration port in accordance with the DOSAGE AND ADMINISTRATION section of the approved prescribing information of the 0.9% Sodium Chloride Injection USP. The port of the sodium chloride bag must be penetrated only one time. Once the bag port is penetrated, it should remain installed on the RUBY Rubidium Elution System for its entire period of use. A maximum use time of 12 hours from the initial port penetration is permitted. Before the next patient, replace the saline bag as part of the mandatory daily quality control procedure. Allow at least 10 minutes between elutions for regeneration of Rb 82. 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. 2.6 Quality Control Testing Procedure Elute with additive-free 0.9% Sodium Chloride Injection USP only. [see Boxed Warning, Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) ]. Replace the saline bag daily as part of the mandatory daily quality control procedure. Use the ionization chamber-type dose calibrator with the elution system (used specifically with the RUBY-FILL Rubidium Rb 82 Generator) for eluate testing. Perform Mandatory Eluate Testing (i.e. Quality Control Testing Procedure) 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 mcCi per mCi (kBq per MBq) Rb 82, or Sr 85 level reaches 0.04 mcCi per mCi (kBq per MBq) Rb 82. 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 Testing Procedure 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: 4. The system uses a correction factor (F) of 0.48 to compensate for the contribution of Sr 85 to the reading. 5. The system calculates the amount of Sr 82 in the sample using the following equation: 6. The system determines if Sr 82 in the eluate exceeds an Alert or Expiration Limit by dividing the mcCi (or kBq) of Sr 82 by the mCi (or MBq) of Rb 82 at End of Elution (see below for further instructions based on the Sr 82 level) 7. The system determines if Sr 85 in the eluate exceeds an Alert or Expiration Limit by multiplying the result obtained in step 6 by (R) as calculated in step 3 (above). The system uses Table 1 to calculate the decay factor for Rb 82 TABLE 1 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 T 1/2 = 65 days, Sr 82 T 1/2 = 25 days) Days RatioFactor Days Ratio Factor Days Ratio Factor 0* 1.00 21 1.43 42 2.05 1 1.02 22 1.46 43 2.08 2 1.03 23 1.48 44 2.12 3 1.05 24 1.51 45 2.15 4 1.07 25 1.53 46 2.19 5 1.09 26 1.56 47 2.23 6 1.11 27 1.58 48 2.27 7 1.13 28 1.61 49 2.30 8 1.15 29 1.64 50 2.34 9 1.17 30 1.67 51 2.38 10 1.19 31 1.70 52 2.43 11 1.21 32 1.73 53 2.47 12 1.23 33 1.76 54 2.51 13 1.25 34 1.79 55 2.55 14 1.27 35 1.82 56 2.60 15 1.29 36 1.85 57 2.64 16 1.31 37 1.88 58 2.69 17 1.34 38 1.91 59 2.73 18 1.36 39 1.95 60 2.78 19 1.38 40 1.98 20 1.41 41 2.01 * Day of Calibration. eq1 eq2 eq4 eq5 2.7 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-calibration), or An eluate Sr 82 level of 0.01 mcCi/mCi (kBq/MBq) Rb 82, or An eluate Sr 85 level of 0.1 mcCi/mCi (kBq/MBq) Rb 82. 2.8 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 Age 1 Generator Age (days) 2 Maximum Rubidium Dose (Delivery Limit) 0 to 17 60 mCi (2220 MBq) 24 50 mCi (1850 MBq) 32 40 mCi (1480 MBq) 42 30 mCi (1110 MBq) 57 20 mCi ( 740 MBq) 1 Estimate is based on a 100 mCi (3700 MBq) Sr 82 generator at calibration. 2 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. 2.9 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 82 Rb 1 (mcGy/MBq) 82 Sr 2 (mcGy/kBq) 85 Sr 2 (mcGy/kBq) Adrenals 2.4 2.9 1.4 Bone surfaces 0.42 29 2.7 Brain 0.14 2.2 0.8 Breast 0.19 1.9 0.5 Gallbladder wall 0.72 2.3 0.8 Gastrointestinal tract Esophagus 3 1.5 2.1 0.6 Stomach wall 0.83 2.1 0.6 Small intestine wall 2.0 2.6 1.1 Colon wall 1.1 9.7 1.2 (ULI wall) 1.1 6.4 1.0 (LLI wall) 1.1 14 1.4 Heart wall 4.0 2.2 0.7 Kidneys 9.3 2.5 0.7 Liver 1.0 2.2 0.7 Lungs 2.6 2.2 0.8 Muscles 0.23 2.2 0.7 Ovaries 0.50 2.8 1.2 Pancreas 2.6 2.5 0.9 Red marrow 0.38 25 2.7 Skin 0.18 1.9 0.5 Spleen 0.18 2.2 0.7 Testes 0.26 2.0 0.5 Thymus 1.5 2.1 0.6 Thyroid 0.31 2.2 0.7 Urinary bladder wall 0.18 5.9 0.8 Uterus 1.0 2.5 0.9 Remaining organs 0.31 - - Effective dose per unit activity 1.1 mcSv/MBq 6.3 mcSv/kBq 1.1 mcSv/kBq 1 Rb 82 doses are averages of rest and stress dosimetry data. To calculate organ doses (mcGy) from Rb 82, multiply the dose coefficient for each organ by the administered activity in MBq. 2 To calculate organ doses attributable to Sr 82 and Sr 85, multiply those dose coefficients by the respective strontium activities associated with the injection. 3 The absorbed dose to the thymus is used as a substitute.

4 CONTRAINDICATIONS RUBY-FILL is contraindicated for use if a solution other than additive-free 0.9% Sodium Chloride Injection USP has been used to elute the generator at any time. Immediately stop the patient infusion and permanently discontinue the use of the affected RUBY-FILL generator whenever the incorrect eluent is used [ see Boxed Warning, Contraindications ( 4 ), Warnings and Precautions ( 5.1 ) ]. RUBY-FILL is contraindicated if a solution other than additive-free 0.9% Sodium Chloride Injection USP has been used to elute the generator at any time. ( 4 )

5 WARNINGS AND PRECAUTIONS •Pharmacologic induction of cardiovascular stress: May be associated with serious adverse reactions such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction, and cerebrovascular events. Perform testing only in setting where cardiac resuscitation equipment and trained staff are readily available. ( 5.3 ) 5.1 High Level Radiation Exposure with Use of Incorrect Eluent Use only additive-free 0.9% Sodium Chloride Injection USP to elute the generator. Apply the provided saline confirmation label to the additive-free 0.9% Sodium Chloride Injection USP bag before use. Additives present in other solutions (particularly calcium ions) expose patients to high levels of radiation by causing the release of large amounts of Sr 82 and Sr 85 into the eluate regardless of the generator’s age or prior use [Dosage and Administration ( 2.1 , 2.5 , 2.6 )] . Immediately stop the patient infusion and discontinue use of the affected RUBY-FILL generator if the incorrect eluent is used and evaluate the patient’s radiation absorbed dose and monitor for the effects of radiation to critical organs such as bone marrow. When solutions containing calcium ions are used to elute the generator, high levels of radioactivity are present in the eluate, even with the subsequent use of additive-free 0.9% Sodium Chloride Injection USP [see Boxed Warning, Dosage and Administration ( 2.9 ), and Contraindications ( 4 )]. 5.2 Excess Radiation Exposure with Failure to Follow the Quality Control Testing Procedure Excess radiation exposure occurs when the Sr 82 and Sr 85 levels in rubidium Rb 82 chloride injections exceed the specified generator eluate limits. Strictly adhere to the quality control testing procedure to minimize radiation exposure to the patient. Stop using the rubidium generator when the expiration limits are reached [see Dosage and Administration ( 2.6 ) and ( 2.7 )]. 5.3 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. 5.4 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 ( 2.1 ) and ( 2.2 )] .

6 ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Jubilant DraxImage Inc., dba Jubilant Radiopharma TM at 1-888-633-5343 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reaction associated with the use of rubidium Rb 82 chloride was identified in clinical trials or post marketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Radiation Exposure High level radiation exposure to the bone marrow has occurred in some patients due to Sr 82 and Sr 85 breakthrough in the eluate when an incorrect solution was used to elute the rubidium Rb 82 generator [see Boxed Warning, Warnings and Precautions ( 5.1 )] . Excess radiation exposure has occurred in some patients who received rubidium Rb 82 chloride injection at clinical sites where generator eluate testing appeared insufficient [see Boxed Warning, Warnings and Precautions ( 5.2 ), Dosage and Administration ( 2.6 )] .

8.1 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 to 4% and 15 to 20%, respectively.