FLUORODOPA F18

11.1 Chemical Characteristics Fluorodopa F 18 Injection is a radioactive diagnostic agent used in PET imaging. The active ingredient 6-[ 18 F] Fluoro-L-3, 4-dihydroxyphenylalanine has the molecular formula of C 9 H 10 FNO 4 with a molecular weight of 214.18, and has the following chemical structure: Fluorodopa F 18 Injection is a sterile, pyrogen-free, clear, colorless solution. Each mL contains between 15.5 MBq/mL to 308.2 MBq/mL (0.42 mCi/mL to 8.33 mCi/mL) of carrier added Fluorodopa F 18 (6-[ 18 F] Fluoro-L-3, 4-dihydroxyphenylalanine) at the end of synthesis (EOS); and does not contain any preservative. There is 12.72 mg acetic acid and 108 mg sodium chloride in 12 mL ±1mL sterile water for injection. The pH of the solution is between 3 and 5. FDOPA Structure 11.2 Physical Characteristics Fluorine F 18 is a cyclotron produced radionuclide that decays by positron emission to Oxygen O 18 (stable) and has a physical half-life of 109.7 minutes. The principal photons useful for imaging are the dual 511 keV gamma photons, which are produced and emitted simultaneously in opposite direction following positron-electron annihilation (Table 2). Table 2. Principal Radiation Emission Data for Fluoride F 18 Radiation/Emission % Per Disintegration Mean Energy Positron(β+) 96.73 249.8 keV Gamma(±) * 193.46 511.0 keV * Produced by positron annihilation 11.3 External Radiation The point source air-kerma coefficient for F 18 is 3.75 × 10 -17 Gy m 2 / (Bq s). The half-value layer (HVL) for the 511 keV photons is 5 mm lead (Pb). The range of attenuation coefficients for this radionuclide as a function of lead shield thickness is shown in Table 3. For example, the interposition of a 9 mm thickness of Pb, with a coefficient of attenuation of 0.25, will decrease the external radiation by 75%. Table 3. Radiation Attenuation of 511 keV Photons by lead (Pb) shielding Shield thickness (Pb) mm Coefficient of Attenuation 0 0.00 5 0.50 9 0.25 15 0.10 29 0.01 39 0.001 52 0.0001 For use in correcting for physical decay of this radionuclide, the fractions remaining at selected intervals after calibration are shown in Table 4. Table 4. Physical Decay Chart for Fluorine F 18 Time Since Calibration Fraction Remaining 0 * 1.000 15 min 0.909 30 min 0.826 60 min 0.683 110 min 0.500 220 min 0.250 440 min 0.060 12 hours 0.011 24 hours 0.0001 * Calibration time 11.1 Chemical Characteristics Fluorodopa F 18 Injection is a radioactive diagnostic agent used in PET imaging. The active ingredient 6-[ 18 F] Fluoro-L-3, 4-dihydroxyphenylalanine has the molecular formula of C 9 H 10 FNO 4 with a molecular weight of 214.18, and has the following chemical structure: Fluorodopa F 18 Injection is a sterile, pyrogen-free, clear, colorless solution. Each mL contains between 15.5 MBq/mL to 308.2 MBq/mL (0.42 mCi/mL to 8.33 mCi/mL) of carrier added Fluorodopa F 18 (6-[ 18 F] Fluoro-L-3, 4-dihydroxyphenylalanine) at the end of synthesis (EOS); and does not contain any preservative. There is 12.72 mg acetic acid and 108 mg sodium chloride in 12 mL ±1mL sterile water for injection. The pH of the solution is between 3 and 5. FDOPA Structure 11.2 Physical Characteristics Fluorine F 18 is a cyclotron produced radionuclide that decays by positron emission to Oxygen O 18 (stable) and has a physical half-life of 109.7 minutes. The principal photons useful for imaging are the dual 511 keV gamma photons, which are produced and emitted simultaneously in opposite direction following positron-electron annihilation (Table 2). Table 2. Principal Radiation Emission Data for Fluoride F 18 Radiation/Emission % Per Disintegration Mean Energy Positron(β+) 96.73 249.8 keV Gamma(±) * 193.46 511.0 keV * Produced by positron annihilation 11.3 External Radiation The point source air-kerma coefficient for F 18 is 3.75 × 10 -17 Gy m 2 / (Bq s). The half-value layer (HVL) for the 511 keV photons is 5 mm lead (Pb). The range of attenuation coefficients for this radionuclide as a function of lead shield thickness is shown in Table 3. For example, the interposition of a 9 mm thickness of Pb, with a coefficient of attenuation of 0.25, will decrease the external radiation by 75%. Table 3. Radiation Attenuation of 511 keV Photons by lead (Pb) shielding Shield thickness (Pb) mm Coefficient of Attenuation 0 0.00 5 0.50 9 0.25 15 0.10 29 0.01 39 0.001 52 0.0001 For use in correcting for physical decay of this radionuclide, the fractions remaining at selected intervals after calibration are shown in Table 4. Table 4. Physical Decay Chart for Fluorine F 18 Time Since Calibration Fraction Remaining 0 * 1.000 15 min 0.909 30 min 0.826 60 min 0.683 110 min 0.500 220 min 0.250 440 min 0.060 12 hours 0.011 24 hours 0.0001 * Calibration time

Fluorodopa F 18 Injection is indicated for use in positron emission tomography (PET) to visualize dopaminergic nerve terminals in the striatum for the evaluation of adult patients with suspected Parkinsonian syndromes (PS). Fluorodopa F 18 PET is an adjunct to other diagnostic evaluations. Fluorodopa F 18 Injection is a radioactive diagnostic agent indicated for use in positron emission tomography (PET) to visualize dopaminergic nerve terminals in the striatum for the evaluation of adult patients with suspected Parkinsonian syndromes (PS). Fluorodopa F 18 PET is an adjunct to other diagnostic evaluations.

• The recommended adult dose is 185 megabecquerels (MBq) [5 millicuries (mCi)] by intravenous injection infused over 1 minute. ( 2.2 ) • Use aseptic techniques and radiation shielding to maintain sterility during all operations involved in the manipulation and administration of Fluorodopa F 18 Injection. ( 2.1 , 2.2 ) • Instruct patients to void immediately before imaging and start imaging at approximately 80 minutes post administration (with a 9 second CT scan for attenuation correction) followed by 3D PET scan from 80 to 100 minutes post administration. ( 2.5 ) • See full prescribing information for additional preparation, administration, imaging and radiation dosimetry information. ( 2 ) 2.1 Radiation Safety - Drug Handling • Handle Fluorodopa F 18 Injection with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions ( 5.1 )] . Use waterproof gloves, effective shielding and appropriate safety measures to avoid unnecessary radiation exposure to the patient, occupational workers, clinical personnel, and other persons. 2.2 Recommended Dosage and Administration Recommended Dose • The recommended dose for adults is 185 megabecquerels (MBq) [5 millicuries (mCi)] administered as an intravenous injection infused over 1 minute. • Minimize the dose of Fluorodopa F 18 Injection consistent with the objectives of the procedure and the nature of the imaging cameras employed. Administration • Use aseptic techniques and radiation shielding during all operations involved in the manipulation and administration of Fluorodopa F 18 Injection. • Calculate the necessary volume to administer based on calibration time and dose. • Inspect Fluorodopa F 18 Injection visually and do not use the drug if the solution contains particulate matter or is discolored. • Measure the patient dose immediately prior to administration in a dose calibrator. • Dispose of unused drug in compliance with applicable regulations. 2.3 Patient Preparation Hydration • Patients must have nothing to eat or drink, except water for 4 hours before administration • To minimize the radiation absorbed dose to the bladder, instruct patient to: o hydrate 4 hours prior to the administration of Fluorodopa F 18 Injection and continue hydration after the study. o void 70 minutes after administration of Fluorodopa F 18 Injection and as frequently thereafter as possible for the next 12 hours. Pre-medication and Medication Withdrawal • Carbidopa blocks systemic/peripheral decarboxylation of Fluorodopa F 18 Injection to increase uptake in the brain. Administer 150 mg of Carbidopa orally at least 60 minutes (and no longer than 120 minutes) prior to the administration of Fluorodopa F 18 Injection. • Instruct the patient to discontinue medications for the treatment of Parkinson’s disease 12 hours prior to administration of Fluorodopa F 18 Injection [see Drug Interactions ( 7 )] . 2.4 Radiation Dosimetry The estimated human absorbed radiation dose for 10 human subjects (8 men and 2 women; mean age 50 ±8.8 yr) from intravenous administration of Fluorodopa F 18 Injection is shown in Table 1. In subjects who voided at 40 min post-injection, the radiation absorbed dose to the bladder wall was 50% lower than the radiation absorbed dose in subjects who voided at 2 hours post-injection. The identified critical organ is the urinary bladder. Table 1. Estimated Absorbed Radiation Dose (mGy/MBq) for Adult Patients after Intravenous Administration of Fluorodopa F 18 Injection a Organ Absorbed Dose per unit activity (mGy/MBq) Urinary bladder wall 0.30 Heart wall 0.01 Pancreas 0.01 Spleen 0.01 Lungs 0.01 Kidneys 0.03 Ovaries 0.02 Uterus 0.03 Lower Large Intestine wall 0.02 Liver 0.01 Gallbladder wall 0.01 Small Intestine 0.01 Upper Large Intestine wall 0.01 Stomach wall 0.01 Adrenals 0.01 Testes 0.01 Red marrow 0.01 Thymus 0.01 Thyroid 0.01 Muscle 0.01 Bone surfaces 0.01 Breast 0.01 Skin 0.01 Brain 0.01 Remaining organs 0.01 Effective dose (mSv/MBq) 0.03 a ICRP Publication 128, Radiation Dose to Patients from Radiopharmaceuticals, Annals of the ICRP , Vol. 44, No. 2S, 2015. 2.5 Imaging Guidelines • Instruct the patient to void immediately before imaging, 70 minutes post administration. • Start imaging at about 80 minutes post administration (with a 9 second CT scan for attenuation correction) followed by 3D PET scan from 80 to 100 minutes post administration. 2.6 Image Interpretation Fluorodopa F 18 PET scans are interpreted visually, based upon the appearance and shape of the putamen and caudate of the striatum. Optimum presentation of the reconstructed images for visual interpretation is transaxial slices parallel to the anterior commissure-posterior commissure (AC-PC) line. Determination of whether an image is negative or positive is made by assessing the shape and intensity of the striatal signal (see Figure 1 and 2). Image interpretation does not involve integration of the image with clinical signs and/or symptoms. Negative Scans: A full crescent shaped putamen and caudate image (see Figure 1). FDOPA uptake is clearly delineated from the background activity in the brain. It is bilaterally symmetrical and of uniform thickness in both caudate and putamen (comma- or crescent-shaped). Figure 1: Negative Scan Positive Scans: A reduction in the size and shape of putamen (unilaterally or bilaterally) or both putamen and caudate (unilaterally or bilaterally). All of the following are considered positive: • FDOPA uptake is asymmetric in the putamen; normal on one side but reduced on the contralateral side with respect to the background, especially in the posterior part. Caudate uptake is symmetrical on both sides and clearly delineated from the background (see Figure 2, A). • FDOPA uptake is bilaterally reduced in the putamen (see Figure 2, B). • FDOPA uptake is bilaterally reduced in the putamen and in the caudate nuclei (see Figure 2, C). Figure 2: Positive Scans A B C FDOPA Negative Scan FDOPA Positive Scan 2.1 Radiation Safety - Drug Handling • Handle Fluorodopa F 18 Injection with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions ( 5.1 )] . Use waterproof gloves, effective shielding and appropriate safety measures to avoid unnecessary radiation exposure to the patient, occupational workers, clinical personnel, and other persons. 2.2 Recommended Dosage and Administration Recommended Dose • The recommended dose for adults is 185 megabecquerels (MBq) [5 millicuries (mCi)] administered as an intravenous injection infused over 1 minute. • Minimize the dose of Fluorodopa F 18 Injection consistent with the objectives of the procedure and the nature of the imaging cameras employed. Administration • Use aseptic techniques and radiation shielding during all operations involved in the manipulation and administration of Fluorodopa F 18 Injection. • Calculate the necessary volume to administer based on calibration time and dose. • Inspect Fluorodopa F 18 Injection visually and do not use the drug if the solution contains particulate matter or is discolored. • Measure the patient dose immediately prior to administration in a dose calibrator. • Dispose of unused drug in compliance with applicable regulations. 2.3 Patient Preparation Hydration • Patients must have nothing to eat or drink, except water for 4 hours before administration • To minimize the radiation absorbed dose to the bladder, instruct patient to: o hydrate 4 hours prior to the administration of Fluorodopa F 18 Injection and continue hydration after the study. o void 70 minutes after administration of Fluorodopa F 18 Injection and as frequently thereafter as possible for the next 12 hours. Pre-medication and Medication Withdrawal • Carbidopa blocks systemic/peripheral decarboxylation of Fluorodopa F 18 Injection to increase uptake in the brain. Administer 150 mg of Carbidopa orally at least 60 minutes (and no longer than 120 minutes) prior to the administration of Fluorodopa F 18 Injection. • Instruct the patient to discontinue medications for the treatment of Parkinson’s disease 12 hours prior to administration of Fluorodopa F 18 Injection [see Drug Interactions ( 7 )] . 2.4 Radiation Dosimetry The estimated human absorbed radiation dose for 10 human subjects (8 men and 2 women; mean age 50 ±8.8 yr) from intravenous administration of Fluorodopa F 18 Injection is shown in Table 1. In subjects who voided at 40 min post-injection, the radiation absorbed dose to the bladder wall was 50% lower than the radiation absorbed dose in subjects who voided at 2 hours post-injection. The identified critical organ is the urinary bladder. Table 1. Estimated Absorbed Radiation Dose (mGy/MBq) for Adult Patients after Intravenous Administration of Fluorodopa F 18 Injection a Organ Absorbed Dose per unit activity (mGy/MBq) Urinary bladder wall 0.30 Heart wall 0.01 Pancreas 0.01 Spleen 0.01 Lungs 0.01 Kidneys 0.03 Ovaries 0.02 Uterus 0.03 Lower Large Intestine wall 0.02 Liver 0.01 Gallbladder wall 0.01 Small Intestine 0.01 Upper Large Intestine wall 0.01 Stomach wall 0.01 Adrenals 0.01 Testes 0.01 Red marrow 0.01 Thymus 0.01 Thyroid 0.01 Muscle 0.01 Bone surfaces 0.01 Breast 0.01 Skin 0.01 Brain 0.01 Remaining organs 0.01 Effective dose (mSv/MBq) 0.03 a ICRP Publication 128, Radiation Dose to Patients from Radiopharmaceuticals, Annals of the ICRP , Vol. 44, No. 2S, 2015. 2.5 Imaging Guidelines • Instruct the patient to void immediately before imaging, 70 minutes post administration. • Start imaging at about 80 minutes post administration (with a 9 second CT scan for attenuation correction) followed by 3D PET scan from 80 to 100 minutes post administration. 2.6 Image Interpretation Fluorodopa F 18 PET scans are interpreted visually, based upon the appearance and shape of the putamen and caudate of the striatum. Optimum presentation of the reconstructed images for visual interpretation is transaxial slices parallel to the anterior commissure-posterior commissure (AC-PC) line. Determination of whether an image is negative or positive is made by assessing the shape and intensity of the striatal signal (see Figure 1 and 2). Image interpretation does not involve integration of the image with clinical signs and/or symptoms. Negative Scans: A full crescent shaped putamen and caudate image (see Figure 1). FDOPA uptake is clearly delineated from the background activity in the brain. It is bilaterally symmetrical and of uniform thickness in both caudate and putamen (comma- or crescent-shaped). Figure 1: Negative Scan Positive Scans: A reduction in the size and shape of putamen (unilaterally or bilaterally) or both putamen and caudate (unilaterally or bilaterally). All of the following are considered positive: • FDOPA uptake is asymmetric in the putamen; normal on one side but reduced on the contralateral side with respect to the background, especially in the posterior part. Caudate uptake is symmetrical on both sides and clearly delineated from the background (see Figure 2, A). • FDOPA uptake is bilaterally reduced in the putamen (see Figure 2, B). • FDOPA uptake is bilaterally reduced in the putamen and in the caudate nuclei (see Figure 2, C). Figure 2: Positive Scans A B C FDOPA Negative Scan FDOPA Positive Scan

None None

Injection site pain occurred with administration based on a review of the published literature. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact The Feinstein Institutes for Medical Research at 516-562-1052 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 practice. No adverse reactions have been reported for Fluorodopa F 18 Injection based on an open-label clinical trial in 68 patients [see Clinical Studies ( 14 ) ] and additional clinical experience in 53 patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval of use of Fluorodopa F 18 Injection outside of the United States. 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. General Disorders and Administration Site Conditions: Pain 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 practice. No adverse reactions have been reported for Fluorodopa F 18 Injection based on an open-label clinical trial in 68 patients [see Clinical Studies ( 14 ) ] and additional clinical experience in 53 patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval of use of Fluorodopa F 18 Injection outside of the United States. 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. General Disorders and Administration Site Conditions: Pain

Aromatic L-amino acid decarboxylase (AADC) inhibitors Prior to Fluorodopa F 18 Injection administration, use of AADC inhibitors (e.g. carbidopa, benserazide etc.) may increase Fluorodopa F 18 bioavailability to the brain by inhibiting peripheral decarboxylase activity and restricting peripheral Fluorodopa F 18 metabolism [see Dosage and Administration ( 2.3 )] . Dopamine agonists, dopamine reuptake inhibitors, dopamine releasing agents (DRAs), peripheral catechol-O-methyltransferase (COMT) inhibitors, and monoamine oxidase (MAO) inhibitors Therapy for Parkinson’s syndromes includes dopamine agonists, dopamine reuptake inhibitors, dopamine releasing agents (DRAs) such as psychostimulants of the amphetamine class, peripheral catechol-O-methyltransferase (COMT) inhibitors, and monoamine oxidase (MAO) inhibitors. Whether discontinuation of these drugs prior to Fluorodopa F 18 administration may minimize the interference with a Fluorodopa F 18 image is not fully known; however, if use of these drugs can be safely suspended, discontinue use 12 hours before administration of Fluorodopa F18 Injection [see Dosage and Administration ( 2.3 )] .