FLYRCADO

11.1 Chemical Characteristics FLYRCADO (flurpiridaz F 18) injection is a radioactive diagnostic drug for intravenous use. The molecular formula of flurpiridaz F 18 is C 18 H 22 Cl 18 FN 2 O 3 , the molecular mass is 367.8, and the structural formula is: Chemically, flurpiridaz F 18 is 2- tert -butyl-4-chloro-5-[[4-(2-( 18 F)fluoranylethoxymethyl)phenyl]methoxy]pyridazin-3-one. FLYRCADO is a sterile, preservative-free, non-pyrogenic, clear, colorless to yellow radioactive solution. Each mL contains 190 MBq to 2,050 MBq (5 mCi to 55 mCi) of flurpiridaz F 18 at end of synthesis, up to 2.3 mcg flurpiridaz, and the following inactive ingredients: 45 mg hydroxypropyl-β-cyclodextrin (as a solubilizer and co-radiostabilizer), 35 mg L-(+)-ascorbic acid (as a radiostabilizer), 8.2 mg sodium hydroxide, and 55.2 mg anhydrous ethanol, in water for injection. The pH of the solution is between 5.5 and 8. Chemical Structure 11.2 Physical Characteristics Fluorine-18 decays by positron (β+) emission and has a half-life of 109.8 minutes. The principal photons useful for diagnostic imaging are the 511 keV gamma photons, resulting from the interaction of the emitted positron with an electron. Principal emission data for fluorine-18 are shown in Table 4. Table 4 – Principal Radiation Emission Data for Fluorine-18 Radiation/Emission % per Disintegration Mean Energy (keV) Positron 96.7 249.8 Gamma 193.5 511 11.3 External Radiation The point source air-kerma rate constant for fluorine-18 is 3.74E-17 Gy m 2 /(Bq s); this coefficient was formerly defined as the specific gamma-ray constant of 5.7 R/hr/mCi at 1 cm. The first half-value thickness of lead (Pb) for fluorine-18 gamma rays is approximately 6 mm. The relative reduction of radiation emitted by fluorine-18 that results from various thicknesses of lead shielding is shown in Table 5. The use of about 8 cm of Pb will decrease the radiation transmission (i.e., exposure) by a factor of about 10,000. Table 5 - Radiation Attenuation of 511 keV Gamma Rays by Lead Shielding Shielding Thickness cm of Lead (Pb) Coefficient of Attenuation 0.6 0.5 2 0.1 4 0.01 6 0.001 8 0.0001

FLYRCADO is indicated for positron emission tomography (PET) myocardial perfusion imaging (MPI) under rest or stress (pharmacologic or exercise) in adult patients with known or suspected coronary artery disease (CAD) to evaluate for myocardial ischemia and infarction. FLYRCADO is a radioactive diagnostic drug indicated for positron emission tomography (PET) myocardial perfusion imaging (MPI) under rest or stress (pharmacologic or exercise) in adult patients with known or suspected coronary artery disease (CAD) to evaluate for myocardial ischemia and infarction. ( 1 )

Administer FLYRCADO via intravenous injection. ( 2.2 ) When rest and stress imaging are conducted on the same day, the recommended administered activities are ( 2.2 ): Rest imaging: 93 MBq to 111 MBq (2.5 mCi to 3 mCi) Pharmacologic stress imaging: 222 MBq to 241 MBq (6 mCi to 6.5 mCi) Exercise stress imaging: 333 MBq to 352 MBq (9 mCi to 9.5 mCi) When rest and stress imaging are conducted over two days, the recommended rest and stress administered activities, for both pharmacologic and exercise stress, are 93 MBq to 111 MBq (2.5 mCi to 3 mCi). ( 2.2 ) See full prescribing information for radiation safety, preparation, administration, imaging, and radiation dosimetry information. ( 2.1 , 2.2 , 2.3 , 2.4 ) 2.1 Radiation Safety – Drug Handling Handle FLYRCADO with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.2) ] . Use waterproof gloves and effective shielding, including lead-glass syringe shields, when handling and administering FLYRCADO. Radioactive drugs should be used by or under the control of healthcare providers who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. 2.2 Recommended Dosage, Preparation, and Administration Instructions Recommended Dosage The recommended activity for each type of examination is presented in Table 1. Administer two doses by intravenous injection, one for rest imaging and one for stress imaging, using either pharmacologic or exercise stress, in either a 1-day or 2-day protocol. If performing a combined exercise/pharmacologic stress protocol, administer the recommended activity for pharmacologic stress. When rest and stress imaging are performed on the same day, the recommended minimum stress activity is 2-fold the rest activity for pharmacologic stress and 3-fold the rest activity for exercise stress to provide adequate image quality and obscure residual signal from the first acquisition. The recommended maximum total volume administered in one day is 6.1 mL. Table 1 – Recommended Administered Activities of FLYRCADO in Adults for Rest and Stress Imaging Using Pharmacologic or Exercise Stress in a 1-Day or 2-Day Protocol Length of Protocol Activity for Rest Imaging Activity for Stress Imaging Pharmacologic Exercise 1 day 93 MBq to 111 MBq (2.5 mCi to 3 mCi) 222 MBq to 241 MBq (6 mCi to 6.5 mCi) 333 MBq to 352 MBq (9 mCi to 9.5 mCi) 2 days 93 MBq to 111 MBq (2.5 mCi to 3 mCi) 93 MBq to 111 MBq (2.5 mCi to 3 mCi) 93 MBq to 111 MBq (2.5 mCi to 3 mCi) Patient Preparation Instruct patients to drink water to ensure adequate hydration prior to administration of FLYRCADO and to continue drinking and voiding frequently during the first hours following administration to reduce radiation exposure [see Warnings and Precautions (5.2) ] . Drug Preparation Use aseptic technique and radiation shielding to withdraw and administer FLYRCADO. Calculate the necessary volume to administer based on calibration time and activity using a suitably calibrated instrument. Visually inspect FLYRCADO for particulate matter and discoloration prior to administration and do not use if either is observed. Ensure the correct syringe is used and has adequate volume (at least 1 mL to 2 mL) so that the activity in the syringe can be administered without excessive dead volume loss. Measure patient dose using a dose calibrator immediately before administration. Do not use and discard FLYRCADO 8 hours after end of synthesis or when the activity falls below the activity requirement at the time of injection, whichever is earlier. FLYRCADO may be diluted aseptically with 0.9% Sodium Chloride Injection, USP. Diluted product should be used within 8 hours after end of synthesis or when the activity falls below the activity requirement at the time of injection, whichever is earlier. Dispose of unused product in a safe manner and in compliance with applicable regulations. Administration Instructions Administer FLYRCADO via intravenous injection as a bolus lasting less than 10 seconds and immediately follow with a flush of 0.9% Sodium Chloride Injection, USP. The minimum time between rest and stress dose administration is: 30 minutes when using pharmacologic stress 60 minutes when using exercise stress When using pharmacologic stress, administer FLYRCADO at the time of peak vasodilation according to the prescribing information for the stress agent, using an intravenous port different from the one used for the stress agent. When using exercise stress, administer FLYRCADO after the patient reaches at least 85% of their age-predicted maximum heart rate or exhibits ischemic signs or symptoms. The patient should then continue to exercise for approximately 1 minute to 2 minutes after the injection. If the patient cannot achieve the target heart rate, the examination may be converted to pharmacologic stress. 2.3 Image Acquisition Instructions For rest and stress imaging, image reconstruction should include attenuation correction. Rest Imaging Begin the PET acquisition 5 minutes after FLYRCADO administration and acquire images for 10 minutes using a scanner in 3D mode. Pharmacologic Stress Imaging Begin the PET acquisition 5 minutes after FLYRCADO administration and acquire images for 10 minutes using a scanner in 3D mode. Optionally, dynamic imaging may be performed, starting immediately prior to the injection of FLYRCADO. Exercise Stress Imaging Once the patient has been positioned on the scanner and respiration has begun to return to normal, begin image acquisition (about 15 minutes to 25 minutes after administration of FLYRCADO). Acquire images for 10 minutes using a scanner in 3D mode. 2.4 Radiation Dosimetry Table 2 shows the estimated radiation absorbed doses per unit of injected activity. Table 2 – Estimated Radiation Absorbed Doses in Organs/Tissues from Intravenous Administration of FLYRCADO in Adults Organ Absorbed Dose per Unit of Administered Activity (mGy/MBq) Rest Pharmacologic Stress The pharmacologic stress agent used was adenosine. Exercise Stress Adrenals 0.016 0.016 0.014 Bone surfaces 0.019 0.019 0.02 Brain 0.025 0.022 0.011 Breasts 0.009 0.009 0.01 Gallbladder Wall 0.017 0.018 0.015 Gastrointestinal Tract Stomach Wall 0.04 0.033 0.024 Small Intestine Wall 0.013 0.012 0.014 Upper Large Intestine Wall 0.013 0.012 0.014 Lower Large Intestine Wall 0.012 0.011 0.014 Heart Wall 0.048 0.09 0.039 Kidneys 0.066 0.057 0.027 Liver 0.039 0.044 0.015 Lungs 0.011 0.012 0.012 Muscle 0.01 0.01 0.012 Ovaries 0.012 0.012 0.014 Pancreas 0.016 0.016 0.015 Red Marrow 0.016 0.018 0.015 Salivary Glands 0.035 0.076 0.007 Skin 0.008 0.008 0.009 Spleen 0.016 0.012 0.013 Testes 0.009 0.009 0.011 Thymus 0.011 0.012 0.013 Thyroid 0.032 0.036 0.014 Urinary Bladder Wall 0.023 0.021 0.016 Uterus 0.012 0.012 0.014 Total Body 0.012 0.012 0.012 Effective Dose (mSv/MBq) 0.019 0.019 0.015 The whole-body effective dose resulting from the administration of maximal activity of FLYRCADO of 111 MBq at rest, 241 MBq during pharmacological stress, and 352 MBq during exercise stress is, respectively, 2.1 mSv, 4.6 mSv, and 5.3 mSv. Under the same conditions, the absorbed dose to the target organ (heart wall) is 5.3 mGy, 22 mGy, and 14 mGy for each administered activity, respectively. The use of a CT scan to calculate attenuation correction for the reconstruction of FLYRCADO PET images (as done in PET/CT imaging) will add radiation exposure.

None. None ( 4 )

The following serious adverse reactions are described elsewhere in the labeling: Risks Associated with Exercise or Pharmacologic Stress [see Warnings and Precautions (5.1) ] Most common adverse reactions occurring during FLYRCADO PET MPI under rest and stress (pharmacologic or exercise) (incidence ≥ 2%) are dyspnea, headache, angina pectoris, chest pain, fatigue, ST segment changes, flushing, nausea, abdominal pain, dizziness, and arrhythmia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GE HealthCare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of FLYRCADO was evaluated in 1,600 subjects in clinical studies, including 1,575 (98%) subjects with known or suspected coronary artery disease and 25 (2%) healthy subjects. All 1,600 subjects were dosed under rest conditions, with a mean dose of 102 MBq (2.8 mCi) FLYRCADO. A total of 1,568 (98%) subjects were also dosed under stress (exercise or pharmacologic) conditions, with a mean activity of 252 MBq (6.8 mCi) FLYRCADO by intravenous route. The demographic characteristics of the study population were 31% female, mean age 62 years (range 19 years to 90 years), 81% White, 11% Black or African American, 1% Asian, and 7% other or unreported race, and 10% Hispanic or Latino, 81% Not Hispanic or Latino, and 9% unreported ethnicity. Stress testing procedures are associated with serious adverse reactions [see Warnings and Precautions (5.1) ] . Adverse reactions occurring in ≥2% subjects receiving FLYRCADO during PET MPI under rest and stress (pharmacologic or exercise) are presented in Table 3. Table 3. Adverse Reactions Reported in ≥2% of Subjects During FLYRCADO PET MPI Under Rest and Stress (Pharmacologic or Exercise) Adverse Reaction FLYRCADO PET MPI Under Rest and Stress (Pharmacologic or Exercise) N=1,600 Includes 32 subjects who received only one dose at rest. % Dyspnea 17 Headache 15 Angina pectoris 10 Chest pain 8 Fatigue 7 ST segment changes 6 Flushing 5 Nausea 4 Abdominal pain 4 Dizziness 4 Arrhythmia 4 Adverse reactions occurring during FLYRCADO PET MPI under rest and stress (pharmacologic or exercise) in <2% of subjects included diarrhea, palpitations, back pain, cardiac conduction disturbance, rash, dysgeusia, cough, hypotension, anxiety, vomiting, pruritus, bronchospasm, dry mouth, blood pressure elevation, syncope, and wheezing.

Storage and Handling Store FLYRCADO at 2°C to 30°C (36°F to 86°F); excursions to -20°C (-4°F) (up to 2 hours) or to 50°C (122°F) (up to 8 hours) may be permitted. Store FLYRCADO within radiation shielding. The product does not contain a preservative. Do not use and discard FLYRCADO 8 hours after end of synthesis or when the activity falls below the radioactivity requirement at the time of injection, whichever is earlier. The expiration date and time are provided on the shield label. Dispose of the product in accordance with all federal, state, and local laws and institutional requirements. This preparation is for use by persons licensed by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State.