ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Injection site pain occurred with administration based on 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 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 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 18 Injection outside of the United States. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.General Disorders and Administration Site Conditions: Pain.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. In dopaminergic nerve terminals in the brain, Fluorodopa (FDOPA) 18 is decarboxylated by amino acid decarboxylase to Fluorodopamine (FDA) 18 and stored in presynaptic vesicles in the brain. The accumulation of 18 FDA in the striatum is visually detected in the PET scan.. 12.2 Pharmacodynamics. Optimal PET imaging is achieved between 75 to 90 minutes after administration of Fluorodopa 18 Injection based on its pharmacokinetics. The relationship between Fluorodopa 18 dose and plasma concentration is not fully characterized.. 12.3 Pharmacokinetics. DistributionFollowing the intravenous administration, Fluorodopa 18 is cleared from the blood with biologic half-life of about to hours. The time course of background brain radioactivity after Fluorodopa 18 was evaluated. 18 activity in the cerebellum was greater than the parietal or occipital cortex during the first 30 minutes after Fluorodopa 18 suggesting regional differences in amino acid transport.EliminationFluorodopa 18 is cleared from the blood and tissue within 24 hours.Metabolism: Fluorodopa 18 is decarboxylated by aromatic amino acid decarboxylase in the striatum to Fluorodopamine 18. Fluorodopamine 18 is also metabolized via monoamine oxidase to yield [18F] 6-fluoro-3,4-dihydroxyphenylacetic acid (18FDOPAC) and subsequently by COMT to yield [18F]6-fluorohomovanillic acid (18FHVA).Elimination: 80% of the radioactivity is eliminated through the urine. Urine radioactivity peaks at about 30 minutes post-injection. The radiation absorbed dose to the bladder wall is reduced by emptying the bladder just before scanning.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. o Lactation: To decrease radiation exposure to nursing infant, advise lactating woman to pump and discard breastmilk for at least 24 hours (12 half-lives) after administration of Fluorodopa 18 Injection. (8.2). 8.1 Pregnancy. Risk SummaryThere are no available data on Fluorodopa 18 Injection use in pregnant women. Additionally, animal reproductive and developmental toxicity studies have not been conducted with Fluorodopa 18 Injection. However, all radiopharmaceuticals, including Fluorodopa 18 Injection, have potential to cause fetal harm depending on the stage of fetal development, and the magnitude of the radiation dose. If considering Fluorodopa 18 Injection administration to pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from the drug and the gestational timing of exposure.The estimated 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 risks of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively, regardless of drug exposure.. 8.2 Lactation. Risk SummaryNo data are available regarding the presence of Fluorodopa 18 Injection in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Exposure of Fluorodopa 18 Injection to breast fed infant can be minimized by temporary discontinuation of breastfeeding [see Clinical Considerations]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Fluorodopa 18 Injection and any potential adverse effects on the breastfed child from Fluorodopa 18 Injection or from the underlying maternal condition.The body of scientific information related to radioactivity decay, drug tissue distribution and drug elimination shows that less than 0.01% of the radioactivity administered remains in the body after 24 hours.Clinical ConsiderationsTo decrease radiation exposure to nursing infant, advise lactating woman to pump and discard breastmilk for at least 24 hours (12 half-lives) after administration of Fluorodopa 18 Injection.. 8.4 Pediatric Use. The safety and effectiveness of Fluorodopa 18 Injection for visualization of dopaminergic neurons in the striatum has not been established in pediatric patients.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of F-18 FDOPA were evaluated in prospective single-arm study conducted at single center that enrolled 68 adult patients with possible Parkinsonian syndrome (PS). In the study, F-18 FDOPA image reads were compared to reference clinical diagnostic standard of Parkinsonian syndrome or non-Parkinsonian syndrome (non-PS) established at to months after the F-18 FDOPA PET scan by movement disorder specialist blinded to F-18 FDOPA PET results. The reference clinical diagnostic standard for PS included Parkinsons disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). These conditions have been associated with dopaminergic neurodegeneration and F-18 FDOPA PET imaging was not designed to distinguish among the conditions. The reference clinical diagnostic standard for non-PS included essential tremor (ET) diagnosis, vascular parkinsonism, drug-induced parkinsonism, and other non-PS diagnoses.Carbidopa (150 mg) was administered orally to patients approximately 60 minutes prior to the administration of Fluorodopa 18 Injection. Each patient was injected mCi F-18 FDOPA (range 4.5-5.5 mCi), and PET images were acquired 80-100 minutes post injection.F-18 FDOPA PET images were evaluated independently by readers blinded to clinical information who had no other role in patient assessment. Patients with at least one cardinal feature of PS were referred to the study by physicians who were uncertain of diagnosis. Thirty-three of these patients had symptoms for years or less. Fifty-six of these patients completed F-18 FDOPA PET imaging and at least month clinical follow-up. Among these 56 patients, 32% were female and 68% were male. Mean patient age was 66 years. Thirty-three patients were categorized as PS, and twenty-three patients were categorized as non-PS based on minimum month clinical follow-up by movement disorder specialist.Table shows the positive percent agreement and negative percent agreement of F-18 FDOPA Injection PET image results with the reference clinical diagnostic standard. Positive percent agreement represents the percent of patients with positive F-18 FDOPA PET images among all the patients with clinical diagnostic reference standard of PS. Negative percent agreement represents the percent of patients with negative F-18 FDOPA PET images among the patients with non-PS clinical diagnostic reference standard.Table 5. Positive and Negative Percent Agreement for F-18 FDOPA Injection PET Imaging n=56 Patients Positive percent agreement Positive test/Clinical PS (95 CI) Negative percent agreement Negative test/Clinical non-PS (95 CI) Reader 24/33 73% (55, 87) 21/23 91% (72, 99) Reader 16/33 49% (31, 67) 21/23 91% (72, 99) Reader 19/33 58% (39, 75) 19/23 83% (61, 94)The effectiveness of F-18 FDOPA PET as screening or confirmatory test and for monitoring disease progression or response to therapy has not been established.

DESCRIPTION SECTION.

11 DESCRIPTION. 11.1 Chemical Characteristics. Fluorodopa 18 Injection is radioactive diagnostic agent used in PET imaging. The active ingredient 6-[18F] Fluoro-L-3, 4-dihydroxyphenylalanine has the molecular formula of C9H10FNO4 with molecular weight of 214.18, and has the following chemical structure:Fluorodopa 18 Injection is 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 18 (6-[18F] 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 and 5.. FDOPA Structure. 11.2 Physical Characteristics. Fluorine 18 is cyclotron produced radionuclide that decays by positron emission to Oxygen 18 (stable) and has 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 18 Radiation/Emission Per Disintegration Mean Energy Positron(+) 96.73 249.8 keV Gamma(+-) 193.46 511.0 keVProduced by positron annihilation. 11.3 External Radiation. The point source air-kerma coefficient for 18 is 3.75 10-17 Gy m2 (Bq s). The half-value layer (HVL) for the 511 keV photons is mm lead (Pb). The range of attenuation coefficients for this radionuclide as function of lead shield thickness is shown in Table 3. For example, the interposition of 9 mm thickness of Pb, with 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 0.00 0.50 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 18 Time Since Calibration Fraction Remaining 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. o The recommended adult dose is 185 megabecquerels (MBq) [5 millicuries (mCi)] by intravenous injection infused over minute. (2.2)o Use aseptic techniques and radiation shielding to maintain sterility during all operations involved in the manipulation and administration of Fluorodopa 18 Injection. (2.1, 2.2)o Instruct patients to void immediately before imaging and start imaging at approximately 80 minutes post administration (with 9 second CT scan for attenuation correction) followed by 3D PET scan from 80 to 100 minutes post administration. (2.5)o See full prescribing information for additional preparation, administration, imaging and radiation dosimetry information. (2). 2.1 Radiation Safety Drug Handling. Handle Fluorodopa 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 Doseo The recommended dose for adults is 185 megabecquerels (MBq) [5 millicuries (mCi)] administered as an intravenous injection infused over minute.o Minimize the dose of Fluorodopa 18 Injection consistent with the objectives of the procedure and the nature of the imaging cameras employed.Administrationo Use aseptic techniques and radiation shielding during all operations involved in the manipulation and administration of Fluorodopa 18 Injection.o Calculate the necessary volume to administer based on calibration time and dose.o Inspect Fluorodopa 18 Injection visually and do not use the drug if the solution contains particulate matter or is discolored.o Measure the patient dose immediately prior to administration in dose calibrator.o Dispose of unused drug in compliance with applicable regulations.. 2.3 Patient Preparation. Hydrationo Patients must have nothing to eat or drink, except water for hours before administrationo To minimize the radiation absorbed dose to the bladder, instruct patient to: hydrate hours prior to the administration of Fluorodopa 18 Injection and continue hydration after the study. void 70 minutes after administration of Fluorodopa 18 Injection and as frequently thereafter as possible for the next 12 hours.Pre-medication and Medication Withdrawalo Carbidopa blocks systemic/peripheral decarboxylation of Fluorodopa 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 18 Injection.o Instruct the patient to discontinue medications for the treatment of Parkinsons disease 12 hours prior to administration of Fluorodopa 18 Injection [see Drug Interactions (7)].. 2.4 Radiation Dosimetry. The estimated human absorbed radiation dose for 10 human subjects (8 men and women; mean age 50 +-8.8 yr) from intravenous administration of Fluorodopa 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 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 18 Injectiona Organ Absorbed Dose per unit activity (mGy/MBq) Urinary bladder wall 0.30Heart wall 0.01Pancreas 0.01Spleen 0.01Lungs 0.01Kidneys 0.03Ovaries 0.02Uterus 0.03Lower Large Intestine wall 0.02Liver 0.01Gallbladder wall 0.01Small Intestine 0.01Upper Large Intestine wall 0.01Stomach wall 0.01Adrenals 0.01Testes 0.01Red marrow 0.01Thymus 0.01Thyroid 0.01Muscle 0.01Bone surfaces 0.01Breast 0.01Skin 0.01Brain 0.01Remaining organs 0.01Effective dose (mSv/MBq) 0.03aICRP 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.o Start imaging at about 80 minutes post administration (with 9 second CT scan for attenuation correction) followed by 3D PET scan from 80 to 100 minutes post administration.. 2.6 Image Interpretation. Fluorodopa 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 and 2). Image interpretation does not involve integration of the image with clinical signs and/or symptoms.Negative Scans: 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 ScanPositive Scans: 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:o 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).o FDOPA uptake is bilaterally reduced in the putamen (see Figure 2, B).o FDOPA uptake is bilaterally reduced in the putamen and in the caudate nuclei (see Figure 2, C).Figure 2: Positive Scans B C. FDOPA Negative Scan. FDOPA Positive Scan.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Aromatic L-amino acid decarboxylase (AADC) inhibitorsPrior to Fluorodopa 18 Injection administration, use of AADC inhibitors (e.g. carbidopa, benserazide etc.) may increase Fluorodopa 18 bioavailability to the brain by inhibiting peripheral decarboxylase activity and restricting peripheral Fluorodopa 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) inhibitorsTherapy for Parkinsons 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 18 administration may minimize the interference with Fluorodopa 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)].