FLYRCADO- flurpiridaz f-18_injection

Flurpiridaz F 18 is an analog of the mitochondrial complex 1 (MC-1) inhibitor, pyridaben. Flurpiridaz F 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. The relationship between flurpiridaz F 18 plasma concentrations and successful imaging was not explored in clinical trials. The pharmacokinetics of flurpiridaz F 18 were evaluated in healthy subjects. Blood radioactivity peaked at 2. 3 minutes with blood clearance followed by a rise and plateau at around 3% of the 296 MBq (8 mCi) flurpiridaz F 18 intravenous dose until 7 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. Distribution Flurpiridaz F 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 1 hour after administration. Elimination Flurpiridaz F 18 and its metabolites were cleared from blood within 48 hours. Metabolism Flurpiridaz F 18 was shown to undergo biotransformation to numerous polar metabolites. Excretion Following intravenous administration of a single dose of 3 Specific Populations No clinically significant differences in the pharmacokinetics of flurpiridaz F 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 B and C) or end stage renal disease on flurpiridaz F 18 pharmacokinetics has not been evaluated.

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. ( 1 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.

Administer FLYRCADO via intravenous injection. 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 See full prescribing information for radiation safety, preparation, administration, imaging, and radiation dosimetry information. 4 Handle FLYRCADO with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5. 2) 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. 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. Table 1 en dash 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 222 MBq to 241 MBq 333 MBq to 352 MBq 2 days 93 MBq to 111 MBq 93 MBq to 111 MBq 93 MBq to 111 MBq 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. 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. 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. Table 2 shows the estimated radiation absorbed doses per unit of injected activity. Table 2 en dash Estimated Radiation Absorbed Doses in Organs/Tissues from Intravenous Administration of FLYRCADO in Adults Organ Absorbed Dose per Unit of Administered Activity Rest Pharmacologic Stress The pharmacologic stress agent used was adenosine. Exercise Stress Adrenals 0. 014 Bone surfaces 0. 011 Breasts 0. 01 Gallbladder Wall 0. 015 Gastrointestinal Tract Stomach Wall 0. 024 Small Intestine Wall 0. 014 Upper Large Intestine Wall 0. 014 Lower Large Intestine Wall 0. 014 Heart Wall 0. 039 Kidneys 0. 027 Liver 0. 015 Lungs 0. 012 Muscle 0. 012 Ovaries 0. 014 Pancreas 0. 015 Red Marrow 0. 015 Salivary Glands 0. 009 Spleen 0. 013 Testes 0. 011 Thymus 0. 013 Thyroid 0. 014 Urinary Bladder Wall 0. 016 Uterus 0. 014 Total Body 0. 012 Effective Dose (mSv/MBq) 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. 6 mSv, and 5. 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.

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. 1 To report SUSPECTED ADVERSE REACTIONS, contact GE HealthCare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. 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 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.

Lactation: Temporarily discontinue breastfeeding. A lactating woman should pump and discard breastmilk for at least 8 hours after FLYRCADO administration. 2 Risk Summary There are no data on use of flurpiridaz F 18 in pregnant women to evaluate for a 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 a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from flurpiridaz F 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 a 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 a background risk of birth defect, loss, or other adverse outcomes. 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. Risk Summary There are no data on the presence of flurpiridaz F 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 a breastfed infant can be minimized by advising a lactating woman to temporarily discontinue breastfeeding and to pump and discard breast milk for a minimum of 8 hours after administration of FLYRCADO. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FLYRCADO and any potential adverse effects on the breastfed child from FLYRCADO or from the underlying maternal condition. Safety and effectiveness of FLYRCADO in pediatric patients have not been established. 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.

NONCLINICAL TOXICOLOGY
Carcinogenesis No carcinogenicity studies of flurpiridaz have been conducted. Mutagenesis Flurpiridaz 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 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. 3) 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 subject''s 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. Study 1 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 a mean age of 64 years. A total of 188 (33%) were female, and 473 (82%) were White, 35 (6%) were Black or African American, 6 (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 a secondary analysis using >=70% stenosis as the threshold for significant CAD are shown. Diagnostic Performance of FLYRCADO PET MPI in Study 1 (N = 578 Includes 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 Standard Reader Sensitivity (95% CI) Specificity (95% CI) Sensitivity (95% CI) Specificity (95% CI) Abbreviations: CI = confidence interval, MPI = myocardial perfusion imaging Reader 1 77% 66% 91% 58% Reader 2 74% 70% 87% 62% Reader 3 89% 53% 97% 44% From a blinded re-evaluation of 60 randomly selected PET MPI images presented during the main reading sessions, intra-reader kappa ranged from 0. 93 for the three readers. Using a 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%. Study 2 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 a mean age of 63 years. A total of 235 (31%) were female, and 619 (82%) were White, 101 (13%) were Black or African American, 8 (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 a secondary analysis using a threshold of >=70% stenosis for significant CAD are shown. Diagnostic Performance of FLYRCADO PET MPI in Study 2 (N = 755) >=50% Stenosis or Confirmed MI Reference Standard >=70% Stenosis or Confirmed MI Reference Standard Reader Sensitivity (95% CI) Specificity (95% CI) Sensitivity (95% CI) Specificity (95% CI) Abbreviations: CI = confidence interval, MI = myocardial infarction, MPI = myocardial perfusion imaging Reader 1 73% 73% 82% 68% Reader 2 63% 86% 72% 80% Reader 3 77% 66% 85% 61% From a blinded re-evaluation of a 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 a 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%.

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