GERIATRIC USE SECTION.

8.5 Geriatric Use. Of 1,600 subjects in clinical studies of FLYRCADO, 720 (45%) were 65 years of age and over and 181 (11%) were 75 years of age or older. No overall differences in safety or effectiveness of FLYRCADO have been observed between patients 65 years of age and older and younger adult patients.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described elsewhere in the labeling:Risks Associated with Exercise or Pharmacologic Stress [see Warnings and Precautions (5.1)] 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 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 mean dose of 102 MBq (2.8 mCi) FLYRCADO. total of 1,568 (98%) subjects were also dosed under stress (exercise or pharmacologic) conditions, with 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 ReactionFLYRCADO PET MPI Under Rest and Stress (Pharmacologic or Exercise)N=1,600Includes 32 subjects who received only one dose at rest. %Dyspnea17Headache15Angina pectoris10Chest pain8Fatigue7ST segment changes6Flushing5Nausea4Abdominal pain4Dizziness4Arrhythmia4Adverse 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo carcinogenicity studies of flurpiridaz have been conducted.. MutagenesisFlurpiridaz did not demonstrate mutagenic potential in an in vitro bacterial reverse mutation assay (Ames test), in an in vitro chromosome aberration assay in Chinese hamster ovary cells, or in an in vivo rat micronucleus assay.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Flurpiridaz 18 is an analog of the mitochondrial complex (MC-1) inhibitor, pyridaben. Flurpiridaz 18 is extracted by the myocardium proportional to the blood flow and binds to heart tissue that has biologically active mitochondria. Therefore, radioactivity in viable myocardium is higher than in infarcted tissue.. 12.2 Pharmacodynamics. The relationship between flurpiridaz 18 plasma concentrations and successful imaging was not explored in clinical trials.. 12.3 Pharmacokinetics. The pharmacokinetics of flurpiridaz 18 were evaluated in healthy subjects. Blood radioactivity peaked at 2.3 minutes with blood clearance followed by rise and plateau at around 3% of the 296 MBq (8 mCi) flurpiridaz 18 intravenous dose until hours post administration. The fluorine-18 radioactivity in blood during the first 15-minutes post administration was associated with flurpiridaz while it was associated with flurpiridaz metabolites thereafter.. DistributionFlurpiridaz 18 distributes to the liver (19% of injected activity), kidneys (9%), brain (8%), and heart wall (3%) about 10 minutes post-dose. The heart wall radioactivity was retained for hour after administration.. EliminationFlurpiridaz 18 and its metabolites were cleared from blood within 48 hours.. MetabolismFlurpiridaz 18 was shown to undergo biotransformation to numerous polar metabolites.. ExcretionFollowing intravenous administration of single dose of 3H-radiolabeled flurpiridaz, 63% of the administered dose was recovered in urine (0% unchanged flurpiridaz) and 30% in feces (0% unchanged flurpiridaz).. Specific PopulationsNo clinically significant differences in the pharmacokinetics of flurpiridaz 18 were observed for age, sex, body mass index, diabetic status, mild hepatic impairment (Child Pugh A), or renal impairment (eGFR >=19 to 89 mL/min). The effect of moderate to severe hepatic impairment (Child Pugh and C) or end stage renal disease on flurpiridaz 18 pharmacokinetics has not been evaluated.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Overview of Clinical Studies. The safety and effectiveness of FLYRCADO were evaluated in two prospective, multicenter, open-label clinical studies in adults with either suspected coronary artery disease (CAD) (Study 1: NCT03354273) or known or suspected CAD (Study 2: NCT01347710).Subjects received two injections of FLYRCADO: one at rest and one during stress [see Dosage and Administration (2.2, 2.3)]. For the FLYRCADO stress injection, subjects received either pharmacologic stress agent or engaged in exercise stress. PET myocardial perfusion imaging (MPI) was performed at both rest and stress using cardiac gating and low-dose CT attenuation correction. Subjects also received rest and stress SPECT MPI using technetium Tc 99m sestamibi or technetium Tc 99m tetrofosmin on different day from the PET MPI. The stress modality was to be the same for PET and SPECT.Stress and rest images were displayed side-by-side for the assessment of perfusion and wall motion abnormalities. Three qualified readers, blinded to clinical data, performed independent assessment of each subjects rest and stress images, with each recording an overall qualitative diagnosis of normal, ischemia, ischemia plus scar, or scar. For analyses of sensitivity and specificity, normal was considered image negative and all other diagnoses were considered image positive.. 14.2 Suspected Coronary Artery Disease. Study evaluated the sensitivity and specificity of FLYRCADO PET MPI for the detection of significant CAD in subjects with suspected CAD who were scheduled for invasive coronary angiography (ICA).A total of 578 subjects were evaluable for effectiveness, having rest and stress imaging and evaluable truth standard data. Subjects ranged in age from 26 years to 88 years, with mean age of 64 years. total of 188 (33%) were female, and 473 (82%) were White, 35 (6%) were Black or African American, (1%) were Asian, and 64 (11%) were other races or not reported. In addition, 79 subjects (14%) reported Hispanic/Latino ethnicity. Pharmacologic stress was performed in 83% of subjects and exercise stress in 17% of subjects.The sensitivity and specificity of FLYRCADO PET MPI for detection of significant CAD, defined as the presence of significant stenosis in at least one major epicardial coronary artery or major branch by quantitative coronary angiography (QCA) are reported in Table 6. Results for both >=50% stenosis and secondary analysis using >=70% stenosis as the threshold for significant CAD are shown.Table 6. Diagnostic Performance of FLYRCADO PET MPI in Study (N 578Includes 12 subjects who had reference standard images categorized as uninterpretable by the central reader but were forced to be diagnosed as positive or negative (2 subjects as positive and 10 subjects as negative).)>=50% Stenosis Reference Standard >=70% Stenosis Reference StandardReaderSensitivity (95% CI)N=249Specificity (95% CI) N=329Sensitivity (95% CI)N=127 Specificity (95% CI)N=449 Abbreviations: CI confidence interval, MPI myocardial perfusion imagingReader 177%(72%, 82%) 66%(61%, 71%) 91%(86%, 96%)58%(54%, 63%)Reader 274%(68%, 79%)70%(65%, 75%)87%(82%, 93%)62%(58%, 67%)Reader 389%(85%, 93%)53%(47%, 58%)97%(94%, 100%)44%(39%, 49%)From blinded re-evaluation of 60 randomly selected PET MPI images presented during the main reading sessions, intra-reader kappa ranged from 0.71 to 0.93 for the three readers.Using 50% stenosis threshold, sensitivity of SPECT MPI was 61% to 76% for the three readers, with the lower bound of the 95% confidence intervals ranging from 55% to 70%, and specificity of SPECT MPI was 51% to 65%, with the lower bound of the 95% confidence intervals ranging from 46% to 60%.. 14.3Known or Suspected Coronary Artery Disease. Study evaluated the sensitivity and specificity of FLYRCADO PET MPI for the detection of significant CAD in subjects with known or suspected CAD who had ICA without intervention within 60 days prior to imaging or were scheduled for ICA.A total of 755 subjects were evaluable for effectiveness, having rest and stress imaging for FLYRCADO PET and evaluable truth standard data. Subjects ranged in age from 36 years to 90 years, with mean age of 63 years. total of 235 (31%) were female, and 619 (82%) were White, 101 (13%) were Black or African American, (1%) were Asian, and 24 (4%) were other races or not reported. Pharmacologic stress was performed in 71% of subjects and exercise stress in 29% of subjects.The sensitivity and specificity of FLYRCADO PET MPI for the detection of significant CAD, defined as the presence of significant stenosis in at least one major epicardial coronary artery or major branch by QCA or as history of myocardial infarction are reported in Table 7. Results for both >=50% stenosis and secondary analysis using threshold of >=70% stenosis for significant CAD are shown.Table 7. Diagnostic Performance of FLYRCADO PET MPI in Study (N 755) >=50% Stenosis or Confirmed MI Reference Standard>=70% Stenosis or Confirmed MI Reference StandardReaderSensitivity (95% CI)N=352Specificity (95% CI) N=403Sensitivity (95% CI)N=245Specificity (95% CI)N=510Abbreviations: CI confidence interval, MI myocardial infarction, MPI myocardial perfusion imagingReader 173%(68%, 78%) 73%(68%, 77%) 82%(77%, 87%)68%(63%, 71%)Reader 263%(57%, 67%)86%(82%, 89%)72%(66%, 78%)80%(77%, 83%)Reader 377%(72%, 80%)66%(62%, 71%)85%(80%, 89%)61%(57%, 66%)From blinded re-evaluation of randomly selected 10% of PET MPI images presented during the main reading sessions, intra-reader agreement ranged from 90% to 95% for the three readers.Using 50% stenosis threshold, sensitivity of SPECT MPI was 43% to 58% for the three readers, with the lower bound of the 95% confidence intervals ranging from 38% to 53%, and specificity for SPECT MPI was 80% to 92%, with the lower bound of the 95% confidence intervals ranging from 76% to 89%.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 mean dose of 102 MBq (2.8 mCi) FLYRCADO. total of 1,568 (98%) subjects were also dosed under stress (exercise or pharmacologic) conditions, with 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 ReactionFLYRCADO PET MPI Under Rest and Stress (Pharmacologic or Exercise)N=1,600Includes 32 subjects who received only one dose at rest. %Dyspnea17Headache15Angina pectoris10Chest pain8Fatigue7ST segment changes6Flushing5Nausea4Abdominal pain4Dizziness4Arrhythmia4Adverse 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. 11.1 Chemical Characteristics. FLYRCADO (flurpiridaz 18) injection is radioactive diagnostic drug for intravenous use. The molecular formula of flurpiridaz 18 is C18H22Cl18FN2O3, the molecular mass is 367.8, and the structural formula is:Chemically, flurpiridaz 18 is 2-tert-butyl-4-chloro-5-[[4-(2-(18F)fluoranylethoxymethyl)phenyl]methoxy]pyridazin-3-one.FLYRCADO is 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 18 at end of synthesis, up to 2.3 mcg flurpiridaz, and the following inactive ingredients: 45 mg hydroxypropyl--cyclodextrin (as solubilizer and co-radiostabilizer), 35 mg L-(+)-ascorbic acid (as 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 (+) emission and has 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 - Principal Radiation Emission Data for Fluorine-18Radiation/Emission% per DisintegrationMean Energy (keV)Positron96.7249.8Gamma193.5511. 11.3 External Radiation. The point source air-kerma rate constant for fluorine-18 is 3.74E-17 Gy m2/(Bq s); this coefficient was formerly defined as the specific gamma-ray constant of 5.7 R/hr/mCi at cm. The first half-value thickness of lead (Pb) for fluorine-18 gamma rays is approximately 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 cm of Pb will decrease the radiation transmission (i.e., exposure) by factor of about 10,000.Table - Radiation Attenuation of 511 keV Gamma Rays by Lead ShieldingShielding Thickness cm of Lead (Pb)Coefficient of Attenuation0.60.520.140.0160.00180.0001.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 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 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 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). 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 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) Rest imaging: 93 MBq to 111 MBq (2.5 mCi to 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 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 DosageThe 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 1-day or 2-day protocol.If performing 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 - Recommended Administered Activities of FLYRCADO in Adults for Rest and Stress Imaging Using Pharmacologic or Exercise Stress in 1-Day or 2-Day ProtocolLength of ProtocolActivity for Rest ImagingActivity for Stress ImagingPharmacologicExercise1 day93 MBq to 111 MBq(2.5 mCi to mCi)222 MBq to 241 MBq(6 mCi to 6.5 mCi)333 MBq to 352 MBq(9 mCi to 9.5 mCi)2 days93 MBq to 111 MBq(2.5 mCi to mCi)93 MBq to 111 MBq(2.5 mCi to mCi)93 MBq to 111 MBq(2.5 mCi to mCi). 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 1-day or 2-day protocol.. If performing 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.. Patient PreparationInstruct 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 PreparationUse aseptic technique and radiation shielding to withdraw and administer FLYRCADO.Calculate the necessary volume to administer based on calibration time and activity using 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 mL to mL) so that the activity in the syringe can be administered without excessive dead volume loss.Measure patient dose using dose calibrator immediately before administration.Do not use and discard FLYRCADO 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 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 safe manner and in compliance with applicable regulations.. Use aseptic technique and radiation shielding to withdraw and administer FLYRCADO.. Calculate the necessary volume to administer based on calibration time and activity using 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 mL to mL) so that the activity in the syringe can be administered without excessive dead volume loss.. Measure patient dose using dose calibrator immediately before administration.. Do not use and discard FLYRCADO 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 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 safe manner and in compliance with applicable regulations.. Administration InstructionsAdminister FLYRCADO via intravenous injection as bolus lasting less than 10 seconds and immediately follow with flush of 0.9% Sodium Chloride Injection, USP.The minimum time between rest and stress dose administration is:30 minutes when using pharmacologic stress60 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 minute to minutes after the injection. If the patient cannot achieve the target heart rate, the examination may be converted to pharmacologic stress.. Administer FLYRCADO via intravenous injection as bolus lasting less than 10 seconds and immediately follow with flush of 0.9% Sodium Chloride Injection, USP.. The minimum time between rest and stress dose administration is:30 minutes when using pharmacologic stress60 minutes when using exercise stress 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 minute to 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 ImagingBegin the PET acquisition minutes after FLYRCADO administration and acquire images for 10 minutes using scanner in 3D mode.. Pharmacologic Stress ImagingBegin the PET acquisition minutes after FLYRCADO administration and acquire images for 10 minutes using scanner in 3D mode.Optionally, dynamic imaging may be performed, starting immediately prior to the injection of FLYRCADO.. Exercise Stress ImagingOnce 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 scanner in 3D mode.. 2.4 Radiation Dosimetry. Table shows the estimated radiation absorbed doses per unit of injected activity.Table - Estimated Radiation Absorbed Doses in Organs/Tissues from Intravenous Administration of FLYRCADO in AdultsOrganAbsorbed Dose per Unit of Administered Activity(mGy/MBq)RestPharmacologic StressThe pharmacologic stress agent used was adenosine. Exercise StressAdrenals0.0160.0160.014Bone surfaces0.0190.0190.02Brain0.0250.0220.011Breasts0.0090.0090.01Gallbladder Wall0.0170.0180.015Gastrointestinal Tract Stomach Wall0.040.0330.024 Small Intestine Wall0.0130.0120.014 Upper Large Intestine Wall0.0130.0120.014 Lower Large Intestine Wall0.0120.0110.014Heart Wall0.0480.090.039Kidneys0.0660.0570.027Liver0.0390.0440.015Lungs0.0110.0120.012Muscle0.010.010.012Ovaries0.0120.0120.014Pancreas0.0160.0160.015Red Marrow0.0160.0180.015Salivary Glands0.0350.0760.007Skin0.0080.0080.009Spleen0.0160.0120.013Testes0.0090.0090.011Thymus0.0110.0120.013Thyroid0.0320.0360.014Urinary Bladder Wall0.0230.0210.016Uterus0.0120.0120.014Total Body0.0120.0120.012Effective Dose (mSv/MBq)0.0190.0190.015The 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 CT scan to calculate attenuation correction for the reconstruction of FLYRCADO PET images (as done in PET/CT imaging) will add radiation exposure.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 190 MBq/mL to 2,050 MBq/mL (5 mCi/mL to 55 mCi/mL) of flurpiridaz 18 at end of synthesis as clear, colorless to yellow solution in shielded multiple-dose vial with up to 30 mL fill volume.. Injection: 190 MBq/mL to 2,050 MBq/mL (5 mCi/mL to 55 mCi/mL) of flurpiridaz 18 at end of synthesis in shielded multiple-dose vial with up to 30 mL fill volume (3).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedFLYRCADO (flurpiridaz 18) injection is clear, colorless to yellow solution containing 190 MBq/mL to 2,050 MBq/mL (5 mCi/mL to 55 mCi/mL) of flurpiridaz 18 at end of synthesis, supplied in shielded multiple-dose vial (NDC 0407-8787-01) with up to 30 mL fill volume.. Storage and HandlingStore FLYRCADO at 2C to 30C (36F to 86F); excursions to -20C (-4F) (up to hours) or to 50C (122F) (up to hours) may be permitted. Store FLYRCADO within radiation shielding. The product does not contain preservative.Do not use and discard FLYRCADO 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.

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. 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 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Adequate HydrationInstruct 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)]. PregnancyInform pregnant women of the risks of fetal exposure to radiation dose if they undergo radionuclide procedure and the potential risk of exposure to ethanol which is present in FLYRCADO [see Use in Specific Populations (8.1)].. LactationAdvise lactating woman to temporarily discontinue breastfeeding and to pump and discard breast milk for at least hours after FLYRCADO administration to minimize radiation exposure to breastfed infant [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of flurpiridaz 18 or its metabolites in human milk or animal milk, the effects on the breastfed infant, or the effects on milk production. Based on clinical guidelines, exposure of FLYRCADO to breastfed infant can be minimized by advising lactating woman to temporarily discontinue breastfeeding and to pump and discard breast milk for minimum of hours after administration of FLYRCADO. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for FLYRCADO and any potential adverse effects on the breastfed child from FLYRCADO or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Flurpiridaz 18 is an analog of the mitochondrial complex (MC-1) inhibitor, pyridaben. Flurpiridaz 18 is extracted by the myocardium proportional to the blood flow and binds to heart tissue that has biologically active mitochondria. Therefore, radioactivity in viable myocardium is higher than in infarcted tissue.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo carcinogenicity studies of flurpiridaz have been conducted.. MutagenesisFlurpiridaz did not demonstrate mutagenic potential in an in vitro bacterial reverse mutation assay (Ames test), in an in vitro chromosome aberration assay in Chinese hamster ovary cells, or in an in vivo rat micronucleus assay.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 30 mL Vial Label. NDC 0407-8787-01 Multiple-Dose Vial Non-Pyrogenic SterileFlyrcado(TM) (flurpiridaz 18) injection 190 MBq/mL to 2,050 MBq/mL(5 mCi/mL to 55 mCi/mL) at end of synthesis Diagnostic For Intravenous Use OnlyCAUTIONRADIOACTIVEMATERIALTotal: MBq (mCi) inmL at on date Concentration: MBq/mL (mCi/mL) Exp Date Exp TimeBatch No.: Date: Vial No.: Store FLYRCADO at 2C to 30C (36F to 86F); excursions to -20C (-4F) (up to hours) or to 50C (122F) (up to hours) may be permitted. Recommended Dosage: See Prescribing InformationDistributed by GE Healthcare Inc., Arlington Heights, IL 60004, U.S.A.Rx ONLY200112-0B. PRINCIPAL DISPLAY PANEL 30 mL Vial Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of FLYRCADO in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The relationship between flurpiridaz 18 plasma concentrations and successful imaging was not explored in clinical trials.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of flurpiridaz 18 were evaluated in healthy subjects. Blood radioactivity peaked at 2.3 minutes with blood clearance followed by rise and plateau at around 3% of the 296 MBq (8 mCi) flurpiridaz 18 intravenous dose until hours post administration. The fluorine-18 radioactivity in blood during the first 15-minutes post administration was associated with flurpiridaz while it was associated with flurpiridaz metabolites thereafter.. DistributionFlurpiridaz 18 distributes to the liver (19% of injected activity), kidneys (9%), brain (8%), and heart wall (3%) about 10 minutes post-dose. The heart wall radioactivity was retained for hour after administration.. EliminationFlurpiridaz 18 and its metabolites were cleared from blood within 48 hours.. MetabolismFlurpiridaz 18 was shown to undergo biotransformation to numerous polar metabolites.. ExcretionFollowing intravenous administration of single dose of 3H-radiolabeled flurpiridaz, 63% of the administered dose was recovered in urine (0% unchanged flurpiridaz) and 30% in feces (0% unchanged flurpiridaz).. Specific PopulationsNo clinically significant differences in the pharmacokinetics of flurpiridaz 18 were observed for age, sex, body mass index, diabetic status, mild hepatic impairment (Child Pugh A), or renal impairment (eGFR >=19 to 89 mL/min). The effect of moderate to severe hepatic impairment (Child Pugh and C) or end stage renal disease on flurpiridaz 18 pharmacokinetics has not been evaluated.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no data on use of flurpiridaz 18 in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.All radiopharmaceuticals, including FLYRCADO, have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering FLYRCADO administration to pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from flurpiridaz 18 and the gestational timing of exposure.FLYRCADO contains ethanol (a maximum daily dose of 337 mg anhydrous ethanol). The lower limit of safety for ethanol use during pregnancy has not been established. Published studies have demonstrated that ethanol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. If considering FLYRCADO administration to pregnant woman, inform the patient about the potential for adverse pregnancy outcomes associated with ethanol exposure during pregnancy.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. 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.

SPL UNCLASSIFIED SECTION.

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.

STORAGE AND HANDLING SECTION.

Storage and HandlingStore FLYRCADO at 2C to 30C (36F to 86F); excursions to -20C (-4F) (up to hours) or to 50C (122F) (up to hours) may be permitted. Store FLYRCADO within radiation shielding. The product does not contain preservative.Do not use and discard FLYRCADO 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Temporarily discontinue breastfeeding. lactating woman should pump and discard breastmilk for at least hours after FLYRCADO administration. (8.2). 8.1 Pregnancy. Risk SummaryThere are no data on use of flurpiridaz 18 in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.All radiopharmaceuticals, including FLYRCADO, have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering FLYRCADO administration to pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from flurpiridaz 18 and the gestational timing of exposure.FLYRCADO contains ethanol (a maximum daily dose of 337 mg anhydrous ethanol). The lower limit of safety for ethanol use during pregnancy has not been established. Published studies have demonstrated that ethanol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. If considering FLYRCADO administration to pregnant woman, inform the patient about the potential for adverse pregnancy outcomes associated with ethanol exposure during pregnancy.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. 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.. 8.2 Lactation. Risk SummaryThere are no data on the presence of flurpiridaz 18 or its metabolites in human milk or animal milk, the effects on the breastfed infant, or the effects on milk production. Based on clinical guidelines, exposure of FLYRCADO to breastfed infant can be minimized by advising lactating woman to temporarily discontinue breastfeeding and to pump and discard breast milk for minimum of hours after administration of FLYRCADO. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for FLYRCADO and any potential adverse effects on the breastfed child from FLYRCADO or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness of FLYRCADO in pediatric patients have not been established.. 8.5 Geriatric Use. Of 1,600 subjects in clinical studies of FLYRCADO, 720 (45%) were 65 years of age and over and 181 (11%) were 75 years of age or older. No overall differences in safety or effectiveness of FLYRCADO have been observed between patients 65 years of age and older and younger adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Risk associated with exercise or pharmacologic stress: Serious adverse reactions such as myocardial infarction, arrhythmia, hypotension, broncho-constriction, stroke, and seizures may occur. Perform stress testing in the setting where cardiac resuscitation equipment and trained staff are readily available. When pharmacologic stress is selected, perform the procedure in accordance with the pharmacologic stress agents prescribing information. (5.1)Radiation risks: Ensure safe handling to minimize radiation exposure to patients and health care providers. (5.2). Risk associated with exercise or pharmacologic stress: Serious adverse reactions such as myocardial infarction, arrhythmia, hypotension, broncho-constriction, stroke, and seizures may occur. Perform stress testing in the setting where cardiac resuscitation equipment and trained staff are readily available. When pharmacologic stress is selected, perform the procedure in accordance with the pharmacologic stress agents prescribing information. (5.1). Radiation risks: Ensure safe handling to minimize radiation exposure to patients and health care providers. (5.2). 5.1 Risks Associated with Exercise or Pharmacologic Stress. Patients evaluated with exercise or pharmacologic stress may experience serious adverse reactions such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction, stroke, and seizure. Perform stress testing in the setting where cardiac resuscitation equipment and trained staff are readily available. When pharmacologic stress is selected as an alternative to exercise, perform the procedure in accordance with the pharmacologic stress agents prescribing information.. 5.2 Radiation Risks. FLYRCADO contributes to patients overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling to minimize radiation exposure to patients and health care providers [see Dosage and Administration (2.1, 2.4)]. Advise patients to hydrate before and after administration and to void frequently after administration.