Fludeoxyglucose F 18

RECENT MAJOR CHANGES Warnings and Precautions: ( 5.1 , 5.2 ) 7/2010 Adverse Reactions ( 6 ) 7/2010

1 INDICATIONS AND USAGE Fludeoxyglucose F 18 Injection USP is indicated for positron emission tomography (PET) imaging in the following settings: Fludeoxyglucose F 18 Injection USP is indicated for positron emission tomography (PET) imaging in the following settings: Oncology: For assessment of abnormal glucose metabolism to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with an existing diagnosis of cancer. Cardiology: For the identification of left ventricular myocardium with residual glucose metabolism and reversible loss of systolic function in patients with coronary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging. Neurology: For the identification of regions of abnormal glucose metabolism associated with foci of epileptic seizures ( 1 ). 1.1 Oncology For assessment of abnormal glucose metabolism to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with an existing diagnosis of cancer. 1.2 Cardiology For the identification of left ventricular myocardium with residual glucose metabolism and reversible loss of systolic function in patients with coronary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging. 1.3 Neurology For the identification of regions of abnormal glucose metabolism associated with foci of epileptic seizures.

1.1 Oncology For assessment of abnormal glucose metabolism to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with an existing diagnosis of cancer.

1.2 Cardiology For the identification of left ventricular myocardium with residual glucose metabolism and reversible loss of systolic function in patients with coronary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging.

1.3 Neurology For the identification of regions of abnormal glucose metabolism associated with foci of epileptic seizures.

2 DOSAGE AND ADMINISTRATION Fludeoxyglucose F18 Injection emits radiation. Use procedures to minimize radiation exposure. Calculate the final dose from the end of synthesis (EOS) time using proper radioactive decay factors. Assay the final dose in a properly calibrated dose calibrator before administration to the patient [see Description ( 11.2 )]. Fludeoxyglucose F 18 Injection emits radiation. Use procedures to minimize radiation exposure. Screen for blood glucose abnormalities. In the oncology and neurology settings, instruct patients to fast for 4 - 6 hours prior to the drug's injection. Consider medical therapy and laboratory testing to assure at least two days of normoglycemia prior to the drug's administration ( 5.2 ). In the cardiology settings, administration of glucose-containing food or liquids (e.g., 50 - 75 grams) prior to the drug's injection facilitates localization of cardiac ischemia ( 2.3 ). Aseptically withdraw Fludeoxyglucose F 18 Injection from its container and administer by intravenous injection ( 2 ). The recommended dose: For adults is 5 - 10 mCi (185 - 370 MBq), in all indicated clinical settings ( 2.1 ). For pediatric patients is 2.6 mCi in the neurology setting ( 2.2 ). Initiate imaging within 40 minutes following drug injection; acquire static emission images 30 - 100 minutes from time of injection ( 2 ). 2.1 Recommended Dose for Adults Within the oncology, cardiology and neurology settings, the recommended dose for adults is 5 - 10 mCi (185 - 370 MBq) as an intravenous injection. 2.2 Recommended Dose for Pediatric Patients Within the neurology setting, the recommended dose for pediatric patients is 2.6 mCi, as an intravenous injection. The optimal dose adjustment on the basis of body size or weight has not been determined [see Use in Special Populations ( 8.4 )]. 2.3 Patient Preparation To minimize the radiation absorbed dose to the bladder, encourage adequate hydration. Encourage the patient to drink water or other fluids (as tolerated) in the 4 hours before their PET study. Encourage the patient to void as soon as the imaging study is completed and as often as possible thereafter for at least one hour. Screen patients for clinically significant blood glucose abnormalities by obtaining a history and/or laboratory tests [see Warnings and Precautions ( 5.2 )]. Prior to Fludeoxyglucose F 18 PET imaging in the oncology and neurology settings, instruct patient to fast for 4 - 6 hours prior to the drug's injection. In the cardiology setting, administration of glucose-containing food or liquids (e.g., 50 - 75 grams) prior to Fludeoxyglucose F 18 Injection facilitates localization of cardiac ischemia. 2.4 Radiation Dosimetry The estimated human absorbed radiation doses (rem/mCi) to a newborn (3.4 kg), 1-year old (9.8 kg), 5-year old (19 kg), 10-year old (32 kg), 15-year old (57 kg), and adult (70 kg) from intravenous administration of Fludeoxyglucose F 18 Injection are shown in Table 1. These estimates were calculated based on human 2 data and using the data published by the International Commission on Radiological Protection 4 for Fludeoxyglucose 18 F. The dosimetry data show that there are slight variations in absorbed radiation dose for various organs in each of the age groups. These dissimilarities in absorbed radiation dose are due to developmental age variations (e.g., organ size, location, and overall metabolic rate for each age group). The identified critical organs (in descending order) across all age groups evaluated are the urinary bladder, heart, pancreas, spleen, and lungs. Table 1. Estimated Absorbed Radiation Doses (rem/mCi) After Intravenous Administration of Fludeoxyglucose F 18 Injection MIRDOSE 2 software was used to calculate the radiation absorbed dose. Assumptions on the biodistribution based on data from Gallagher et al. 1 and Jones et al. 2 Organ Newborn (3.4 kg) 1-year old (9.8 kg) 5-year old (19 kg) 10-year old (32 kg) 15-year old (57 kg) Adult (70 kg) Bladder wall The dynamic b …

3 DOSAGE FORMS AND STRENGTHS Multiple-dose glass vial containing 0.74 – 8.88 GBq (20 - 240 mCi/mL) of Fludeoxyglucose F 18 Injection USP and 4.5 mg of sodium chloride in citrate buffer (approximately 29 mL volume) for intravenous administration. Ethanol (3 mg/mL) is used as an antioxidant in Fludeoxyglucose F 18 Injection USP. The pH of the solution is between 4.5 and 7.5. Multiple-dose glass vial containing 20 - 240 mCi/mL (0.74 – 8.88 GBq) of Fludeoxyglucose F 18 Injection USP and 4.5 mg of sodium chloride in citrate buffer (approximately 29 mL volume), for intravenous administration ( 3 ). Ethanol (3 mg/mL) is used as an antioxidant in Fludeoxyglucose F 18 Injection USP. The pH of the solution is between 4.5 and 7.5.

4 CONTRAINDICATIONS None. None ( 4 ).

6 ADVERSE REACTIONS Hypersensitivity reactions with pruritus, edema and rash have been reported in the postmarketing setting. Have emergency resuscitation equipment and personnel immediately available. Hypersensitivity reactions have occurred; have emergency resuscitation equipment and personnel immediately available (6). To report SUSPECTED ADVERSE REACTIONS, contact The University of Utah DBA Cyclotron Radiochemistry Lab Huntsman Cancer Institute at 801-581-8745 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS The possibility of interactions of Fludeoxyglucose F 18 Injection USP with other drugs taken by patients undergoing PET imaging has not been studied.

8 USE IN SPECIAL POPULATIONS Lactation: Temporarily discontinue breastfeeding. A lactating woman should pump and discard breastmilk for 9 hours after Fludeoxyglucose F 18 Injection ( 8.2 ) Pediatric Use: Safety and effectiveness in pediatric patients have not been established in the oncology and cardiology settings ( 8.4 ). 8.1 Pregnancy Risk Summary Data from published case series and case reports describe Fludeoxyglucose F 18 Injection crossing the placenta with uptake by the fetus (see Data). All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. However, published studies that describe Fludeoxyglucose F 18 Injection use in pregnant women have not identified a risk of drug-associated major birth defects, miscarriage, or adverse maternal or fetal outcomes. If considering Fludeoxyglucose F 18 Injection administration to a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from Fludeoxyglucose F 18 Injection 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 risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Human Data Data from published case series and case reports describe Fludeoxyglucose F 18 Injection crossing the placental barrier and visualization of radioactivity throughout the body of the fetus. The estimated fetal absorbed radiation dose from the maximum labeled dose (370 MBq) of Fludeoxyglucose F 18 was 10mGy with first trimester exposure to PET alone and 20mGy with first trimester exposure to PET/CT scan combination. Long-term adverse radiation effects to a child exposed to Fludeoyxglucose F 18 Injection in utero are unknown. No adverse fetal effects or radiation-related risks have been identified for diagnostic procedures involving less than 50mGy, which represents less than 20mGy fetal doses. 8.2 Lactation Risk Summary A published case report and case series show the presence of Fludeoxyglucose F 18 Injection in human milk following administration. There are no data on the effects of Fludeoxyglucose F 18 Injection on the breastfed infant or the effects on milk production. Exposure of Fludeoxyglucose F 18 Injection to a breastfed 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 Fludeoxyglucose F 18 Injection, any potential adverse effects on the breastfed child from Fludeoxyglucose F 18 Injection or from the underlying maternal condition. Clinical Considerations To decrease radiation exposure to the breastfed infant, advise a lactating woman to pump and discard breastmilk and avoid close (breast) contact with the infant for at least 9 hours after the administration of Fludeoxyglucose F 18 Injection. 8.4 Pediatric Use The safety and effectiveness of Fludeoxyglucose F 18 Injection in pediatric patients with epilepsy is established on the basis of studies in adult and pediatric patients. In pediatric patients with epilepsy, the recommended dose is 2.6 mCi. The optimal dose adjustment on the basis of body size or weight has not been determined. In the oncology or cardiology settings, the safety and effectiveness of Fludeoxyglucose F 18 Injection have not been established in pediatric patients.

8.1 Pregnancy Risk Summary Data from published case series and case reports describe Fludeoxyglucose F 18 Injection crossing the placenta with uptake by the fetus (see Data). All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitud …

12.1 Mechanism of Action Fludeoxyglucose F 18 is a glucose analog that concentrates in cells that rely upon glucose as an energy source, or in cells whose dependence on glucose increases under pathophysiological conditions. Fludeoxyglucose F 18 is transported through the cell membrane by facilitative glucose transporter proteins and is phosphorylated within the cell to [ 18 F] FDG-6-phosphate by the enzyme hexokinase. Once phosphorylated it cannot exit until it is dephosphorylated by glucose-6-phosphatase. Therefore, within a given tissue or pathophysiological process, the retention and clearance of Fludeoxyglucose F 18 reflect a balance involving glucose transporter, hexokinase and glucose-6-phosphatase activities. When allowance is made for the kinetic differences between glucose and Fludeoxyglucose F 18 transport and phosphorylation (expressed as the ''lumped constant'' ratio), Fludeoxyglucose F 18 is used to assess glucose metabolism. In comparison to background activity of the specific organ or tissue type, regions of decreased or absent uptake of Fludeoxyglucose F 18 reflect the decrease or absence of glucose metabolism. Regions of increased uptake of Fludeoxyglucose F 18 reflect greater than normal rates of glucose metabolism.

11 DESCRIPTION 11.1 Chemical Characteristics Fludeoxyglucose F 18 Injection is a positron emitting radiopharmaceutical that is used for diagnostic purposes in conjunction with positron emission tomography (PET) imaging. The active ingredient 2-deoxy-2-[ 18 F]fluoro-D-glucose has the molecular formula of C 6 H 11 18 FO 5 with a molecular weight of 181.26, and has the following chemical structure: Fludeoxyglucose F 18 Injection is provided as a ready to use sterile, pyrogen free, clear, colorless citrate buffered solution. Each mL contains between 0.740 to 11.1GBq (20.0-300 mCi) of 2-deoxy-2-[ 18 F]fluoro-D-glucose at the EOS, 4.5 mg of sodium chloride in citrate buffer. The pH of the solution is between 4.5 and 7.5. The solution is packaged in a multiple-dose glass vial and does not contain any preservative. image of FDG 11.2 Physical Characteristics Fluorine F 18 decays by emitting positron 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 “annihilation” gamma photons, that are produced and emitted simultaneously in opposite direction when the positron interacts with an electron (Table 2). Table 2. Principal Radiation Emission Data for Fluorine F 18 Radiation/Emission % Per Disintegration Mean Energy Positron(ß+) 96.73 249.8 keV Gamma(±)* 193.46 511.0 keV *Produced by positron annihilation From: Kocher, D.C. Radioactive Decay Tables DOE/TIC-I 1026, 89 (1981) The specific gamma ray constant (point source air kerma coefficient) for fluorine F 18 is 5.7 R/hr/mCi (1.35 x 10 -6 Gy/hr/kBq) at 1 cm. The half-value layer (HVL) for the 511 keV photons is 4 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 an 8 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 4 0.50 8 0.25 13 0.10 26 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 Minutes Fraction Remaining 0* 1.000 15 0.909 30 0.826 60 0.683 110 0.500 220 0.250 *calibration time

11.1 Chemical Characteristics Fludeoxyglucose F 18 Injection is a positron emitting radiopharmaceutical that is used for diagnostic purposes in conjunction with positron emission tomography (PET) imaging. The active ingredient 2-deoxy-2-[ 18 F]fluoro-D-glucose has the molecular formula of C 6 H 11 18 FO 5 with a molecular weight of 181.26, and has the following chemical structure: Fludeoxyglucose F 18 Injection is provided as a ready to use sterile, pyrogen free, clear, colorless citrate buffered solution. Each mL contains between 0.740 to 11.1GBq (20.0-300 mCi) of 2-deoxy-2-[ 18 F]fluoro-D-glucose at the EOS, 4.5 mg of sodium chloride in citrate buffer. The pH of the solution is between 4.5 and 7.5. The solution is packaged in a multiple-dose glass vial and does not contain any preservative. image of FDG

11.2 Physical Characteristics Fluorine F 18 decays by emitting positron 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 “annihilation” gamma photons, that are produced and emitted simultaneously in opposite direction when the positron interacts with an electron (Table 2). Table 2. Principal Radiation Emission Data for Fluorine F 18 Radiation/Emission % Per Disintegration Mean Energy Positron(ß+) 96.73 249.8 keV Gamma(±)* 193.46 511.0 keV *Produced by positron annihilation From: Kocher, D.C. Radioactive Decay Tables DOE/TIC-I 1026, 89 (1981) The specific gamma ray constant (point source air kerma coefficient) for fluorine F 18 is 5.7 R/hr/mCi (1.35 x 10 -6 Gy/hr/kBq) at 1 …

16 HOW SUPPLIED Fludeoxyglucose F18 Injection, USP is supplied in a multi-dose, capped 30 mL glass vial containing between 0.740 GBq/mL–11.1 GBq/mL (20 mCi/mL—300 mCi/mL), of no carrier added 2‐deoxy-2-[F 18] fluoro-D-glucose, at end of synthesis, in approximately 20 mL. The contents of each vial are sterile, pyrogen-free and preservative-free. NDC 73410-003-01 This radiopharmaceutical is licensed by the State of New York, Department Of Health, Bureau of Environmental Radiation Protection, for distribution to persons licensed pursuant to New York's Regulatory Code for Radioactive material specified in Chapter 1-‐Part 16 of the State Sanitary Code, as appropriate, or under equivalent licenses of an Agreement State or Licensing State. Storage Store the Fludeoxyglucose F18 Injection vial upright in a lead shielded container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Store and dispose of Fludeoxyglucose F18 Injection in accordance with the regulations and a general license, or its equivalent, of an Agreement State or a Licensing State. The expiration date and time are provided on the container label. Use Fludeoxyglucose F18 Injection within 12 hours from the EOS time.