Fluorodopa

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION • 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) …

3 DOSAGE FORMS AND STRENGTHS Injection: clear, colorless solution containing 15.5 MBq/mL to 308.2 MBq/mL (0.42 mCi/mL to 8.33 mCi/mL) of Fluorodopa F 18 Injection, at calibration time in a multiple-dose glass vial. Injection: clear, colorless solution in a multiple-dose glass vial containing 15.5 MBq/mL to 308.2 MBq/mL (0.42 mCi/mL to 8.33 mCi/mL) of Fluorodopa F 18 Injection. ( 3 )

4 CONTRAINDICATIONS None None

6 ADVERSE REACTIONS 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

7 DRUG INTERACTIONS 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 )] .

8 USE IN SPECIFIC POPULATIONS • Lactation: To decrease radiation exposure to a nursing infant, advise a lactating woman to pump and discard breastmilk for at least 24 hours (12 half-lives) after administration of Fluorodopa F 18 Injection. ( 8.2 ) 8.1 Pregnancy Risk Summary There are no available data on Fluorodopa F 18 Injection use in pregnant women. Additionally, animal reproductive and developmental toxicity studies have not been conducted with Fluorodopa F 18 Injection. However, all radiopharmaceuticals, including Fluorodopa F 18 Injection, have a potential to cause fetal harm depending on the stage of fetal development, and the magnitude of the radiation dose. If considering Fluorodopa F 18 Injection administration to a 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 a 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 2 to 4% and 15 to 20%, respectively, regardless of drug exposure. 8.2 Lactation Risk Summary No data are available regarding the presence of Fluorodopa F 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 F 18 Injection to a 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 mother’s clinical need for Fluorodopa F 18 Injection and any potential adverse effects on the breastfed child from Fluorodopa F 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 Considerations To decrease radiation exposure to a nursing infant, advise a lactating woman to pump and discard breastmilk for at least 24 hours (12 half-lives) after administration of Fluorodopa F 18 Injection. 8.4 Pediatric Use The safety and effectiveness of Fluorodopa F 18 Injection for visualization of dopaminergic neurons in the striatum has not been established in pediatric patients.

8.1 Pregnancy Risk Summary There are no available data on Fluorodopa F 18 Injection use in pregnant women. Additionally, animal reproductive and developmental toxicity studies have not been conducted with Fluorodopa F 18 Injection. However, all radiopharmaceuticals, including Fluorodopa F 18 Injection, have a potential to cause fetal harm depending on the stage of fetal development, and the magnitude of the radiation dose. If considering Fluorodopa F 18 Injection administration to a 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 a 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 2 to 4% and 15 to 20%, respectively, regardless of drug exposure.

8.2 Lactation Risk Summary No data are available regarding the presence of Fluorodopa F 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 F 18 Injection to a breast fed infant can be minimized by temporary discontinuation of breastfeeding [see Clinical Considerations] . …

11 DESCRIPTION 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 …

16 HOW SUPPLIED/STORAGE AND DRUG HANDLING Fluorodopa F 18 Injection (NDC 13267-345-56) is supplied as a clear, colorless injection in a septum capped glass vial containing between 15.5 MBq/mL to 308.2 MBq/mL (0.42 mCi/mL to 8.33 mCi/mL), of Fluorodopa F 18 at calibration time, in 12 mL ±1mL. Storage Store the Fluorodopa F 18 Injection vial upright in a lead shielded container at 25°C (77°F); excursions permitted between 15oC to 30°C (59oF to 86°F). Avoid direct light. The expiration date and time are provided on the container label. Use Fluorodopa F 18 Injection within 10 hours from the time of the end of synthesis (EOS). Handling This radiopharmaceutical is for distribution and use by persons licensed authorized by the U.S. Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State. Store and dispose of Fluorodopa F 18 in compliance with the appropriate regulations of the government agency authorized to license the use of this radionuclide.