Sodium Fluoride

1 INDICATIONS AND USAGE Sodium Fluoride F-18 Injection, USP, is indicated for diagnostic positron emission tomography (PET) imaging of bone to define areas of altered osteogenic activity. Sodium Fluoride F-18 Injection, USP, is a radioactive diagnostic agent for positron emission tomography (PET) indicated for imaging of bone to define areas of altered osteogenic activity ( 1 ).

2 DOSAGE AND ADMINISTRATION • Sodium Fluoride F 18 Injection emits radiation and must be handled with appropriate safety measures. ( 2.1 ) • Administer 300-450 MBq (8-12 mCi) as an intravenous injection in adults. ( 2.4 ) • Administer approximately 2.1 MBq/kg in children with a minimum of 19 MBq (0.5 mCi) and a maximum of 148 MBq (4 mCi) as an intravenous injection. ( 2.5 ) • Imaging can begin 1-2 hours after administration; optimally at one hour post administration. ( 2.7 ) • Encourage patients to void immediately prior to imaging the lumbar spine and bony pelvis. ( 2.7 ) 2.1 Radiation Safety - Drug Handling • Wear waterproof gloves and effective shielding when handling Sodium Fluoride F 18 Injection. Use appropriate safety measures, including shielding, consistent with proper patient management to avoid unnecessary radiation exposure to the patient, occupational workers, clinical personnel, and other persons. • Radiopharmaceuticals should be used by or under the control of physicians 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. • Use aseptic technique to maintain sterility during all operations involved in the manipulation and administration of Sodium Fluoride F 18 Injection. • The dose of Sodium Fluoride F 18 Injection should be minimized consistent with the objectives of the procedure, and the nature of the radiation detection devices employed. • The final dose for the patient should be calculated using proper decay factors from the time of End of Synthesis (EOS), and measured by a suitable radioactivity calibration system before administration [see Description ( 11.2 )] . 2.2 Radiation Safety - Patient Preparation • To minimize radiation-absorbed dose to the bladder, encourage adequate hydration. Encourage the patient to ingest at least 500 mL of fluid immediately prior and subsequent to the administration of Sodium Fluoride F 18 Injection. • Encourage the patient to void one-half hour after administration of Sodium Fluoride F 18 Injection and as frequently thereafter as possible for the next 12 hours. 2.3 Drug Preparation and Administration • Calculate the necessary volume to administer based on calibration time and dose. • Inspect Sodium Fluoride F 18 Injection visually for particulate matter and discoloration before administration, whenever solution and container permit. • Do not administer Sodium Fluoride F 18 Injection containing particulate matter or discoloration; dispose of these unacceptable or unused preparations in a safe manner, in compliance with applicable regulations. • Aseptically withdraw Sodium Fluoride F 18 Injection from its container. 2.4 Recommended Dose for Adults Administer 300-450 MBq (8-12 mCi) as an intravenous injection. 2.5 Recommended Dose for Pediatric Patients In reported clinical experience in approximately 100 children, weight based doses (2.1 MBq/kg) ranging from 19 MBq-148 MBq (0.5 mCi-4 mCi) were used. 2.6 Radiation Dosimetry The age/weight-based estimated absorbed radiation doses (mGy/MBq) from intravenous injection of Sodium Fluoride F 18 Injection are shown in Table 1. These estimates were calculated based on human data and using the data published by the Nuclear Regulatory Commission [1] and the International Commission on Radiological Protection for Sodium Fluoride Injection [2]. The bone, bone marrow, and urinary bladder are considered target and critical organs. Table 1. Estimated Absorbed Radiation Doses after Intravenous Administration of Sodium Fluoride F 18 Injection, USP Organ Estimated Radiation Dose mGy/MBq Adult 70 kg [1] 15 year 56.8 kg [2] 10 year 33.2 kg [2] 5 year 19.8 kg [2] 1 year 9.7 kg [2] Adrenals 0.0062 0.012 0.018 0.028 0.052 Brain 0.0056 N/A N/A N/A N/A Bone surfaces 0.060 0.050 0.079 0.13 0.30 Breasts 0.0028 0.0061 0.0097 0.015 0.030 Gallbladder wall 0.0044 N/A N/A …

3 DOSAGE FORMS AND STRENGTHS Multiple-dose vial containing 370-7,400 MBq/mL (10-200 mCi/mL) at EOS reference time of no-carrier-added sodium fluoride F 18 in aqueous 0.9% sodium chloride solution. Sodium Fluoride F 18 Injection, USP is a clear, colorless, sterile, pyrogen-free, and preservative-free solution for intravenous administration. Multiple-dose vial containing 370-7,400 MBq/mL (10-200 mCi/mL) of no-carrier-added sodium fluoride F 18 at the end of synthesis (EOS) reference time in aqueous 0.9% sodium chloride solution ( 3 ). Sodium Fluoride F 18 Injection, USP is a clear, colorless, sterile, pyrogen-free, and preservative-free solution for intravenous administration.

4 CONTRAINDICATIONS None None ( 4 ).

6 ADVERSE REACTIONS No adverse reactions have been reported for Sodium Fluoride F 18 Injection, USP based on a review of the published literature, publicly available reference sources, and adverse drug reaction reporting systems. However, the completeness of these sources is not known. No adverse reactions have been reported for Sodium Fluoride F 18 Injection, USP based on a review of the published literature, publicly available reference sources, and adverse drug reaction reporting systems. 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 .

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

8 USE IN SPECIFIC POPULATIONS • Pregnancy: No human or animal data. Any radiopharmaceutical, including Sodium Fluoride F 18 Injection, USP may cause fetal harm. Use only if clearly needed. ( 8.1 ) • Nursing: A decision should be made whether to interrupt nursing after Sodium Fluoride F 18 Injection, USP administration or not to administer Sodium Fluoride F 18 Injection, USP taking into consideration the importance of the drug to the mother. ( 8.3 ) • Pediatrics: Children are more sensitive to radiation and may be at higher risk of cancer from Sodium Fluoride F 18 Injection, USP. ( 8.4 ) 8.1 Pregnancy Pregnancy Category C Any radiopharmaceutical including Sodium Fluoride F 18 Injection, USP has a potential to cause fetal harm. The likelihood of fetal harm depends on the stage of fetal development, and the radionuclide dose. Animal reproductive and developmental toxicity studies have not been conducted with Sodium Fluoride F 18 Injection, USP. Prior to the administration of Sodium Fluoride F 18 Injection, USP to women of childbearing potential, assess for presence of pregnancy. Sodium Fluoride F 18 Injection, USP should be given to a pregnant woman only if clearly needed. 8.3 Nursing Mothers It is not known whether Sodium Fluoride F 18 Injection, USP is excreted into human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to interrupt nursing after administration of Sodium Fluoride F 18 Injection, USP or not to administer Sodium Fluoride F 18 Injection, USP, taking into account the importance of the drug to the mother. The body of scientific information related to radioactive decay, drug tissue distribution, and drug elimination shows that less than 0.01% of the radioactivity administered remains in the body after 24 hours (12 half-lives). To minimize the risks to a nursing infant, interrupt nursing for at least 24 hours. 8.4 Pediatric Use In reported clinical experience in approximately 100 children, weight based doses (2.1 MBq/kg) ranging from 18.5 MBq-148 MBq (0.5 mCi-4 mCi) were used. Sodium Fluoride F 18 was shown to localize to areas of bone turnover including rapidly growing epiphyses in developing long bones. Children are more sensitive to radiation and may be at higher risk of cancer from Sodium Fluoride F 18 Injection, USP.

8.1 Pregnancy Pregnancy Category C Any radiopharmaceutical including Sodium Fluoride F 18 Injection, USP has a potential to cause fetal harm. The likelihood of fetal harm depends on the stage of fetal development, and the radionuclide dose. Animal reproductive and developmental toxicity studies have not been conducted with Sodium Fluoride F 18 Injection, USP. Prior to the administration of Sodium Fluoride F 18 Injection, USP to women of childbearing potential, assess for presence of pregnancy. Sodium Fluoride F 18 Injection, USP should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers It is not known whether Sodium Fluoride F 18 Injection, USP is excreted into human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to interrupt nursing after administration of Sodium Fluoride F 18 Injection, USP or not to administer Sodium Fluoride F 18 Injection, USP, taking into account the importance of the drug to the mother. The body of scientific information related to radioactive decay, drug tissue distribution, and drug elimination shows that less than 0.01% of the radioactivity administered remains in the body after 24 hours (12 half-lives). To minimize the risks to a nursing infant, interrupt nursing for at least 24 hours.

8.4 Pediatric Use In reported clinical experience in approximately 100 children, weight based doses (2.1 MBq/kg) ranging from 18.5 MBq-148 MBq (0.5 mCi-4 mCi) were used. Sodium Fluoride F 18 was shown to localize to areas of bone turnove …

12.1 Mechanism of Action Fluoride F 18 ion normally accumulates in the skeleton in an even fashion, with greater deposition in the axial skeleton (e.g., vertebrae and pelvis) than in the appendicular skeleton and greater deposition in the bones around joints than in the shafts of long bones.

11 DESCRIPTION 11.1 Chemical Characteristics Sodium Fluoride F 18 Injection, USP is a positron emitting radiopharmaceutical, containing no-carrier-added, radioactive fluoride F 18 that is used for diagnostic purposes in conjunction with PET imaging. It is administered by intravenous injection. The active ingredient, sodium fluoride F 18, has the molecular formula Na[ 18 F] with a molecular weight of 40.99, and has the following chemical structure: Na + 18 F - Sodium Fluoride F 18 Injection, USP is provided as a ready-to-use, isotonic, sterile, pyrogen-free, preservative-free, clear, and colorless solution. Each mL of the solution contains between 740 MBq to 22,200 MBq (20 mCi to 600 mCi) sodium fluoride F 18, at the EOS reference time, in 0.9% aqueous sodium chloride. The pH of the solution is between 4.5 and 8. The solution is presented in 25 mL multiple-dose glass vials with variable total volume and total radioactivity in each vial. 11.2 Physical Characteristics Fluorine F 18 decays by positron (β+) emission and has a half-life of 109.7 minutes. Ninety-seven percent of the decay results in emission of a positron with a maximum energy of 633 keV and 3% of the decay results in electron capture with subsequent emission of characteristic X-rays of oxygen. The principal photons useful for diagnostic imaging are the 511 keV gamma photons, resulting from the interaction of the emitted positron with an electron (Table 2). Fluorine F 18 atom decays to stable 18 O-oxygen. Table 2. Principal 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 [3] Kocher, D.C. Radioactive Decay Data Tables DOE/TIC-11026, 69, 1981. The specific gamma ray constant for fluoride 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 4.1 mm lead (Pb). A range of values for the attenuation of radiation results from the interposition of various thickness of Pb. The range of attenuation coefficients for this radionuclide is shown in Table 3. For example, the interposition of an 8.3 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 Table 4 lists the fraction of radioactivity remaining at selected time intervals from the calibration time. This information may be used to correct for physical decay of the radionuclide. Table 4. Physical Decay Chart for Fluoride F 18 Time Since Calibration Fraction Remaining 0* 1.00 15 minutes 0.909 30 minutes 0.826 60 minutes 0.683 110 minutes 0.500 220 minutes 0.250 440 minutes 0.060 12 hours 0.011 24 hours 0.0001 *Calibration time

11.1 Chemical Characteristics Sodium Fluoride F 18 Injection, USP is a positron emitting radiopharmaceutical, containing no-carrier-added, radioactive fluoride F 18 that is used for diagnostic purposes in conjunction with PET imaging. It is administered by intravenous injection. The active ingredient, sodium fluoride F 18, has the molecular formula Na[ 18 F] with a molecular weight of 40.99, and has the following chemical structure: Na + 18 F - Sodium Fluoride F 18 Injection, USP is provided as a ready-to-use, isotonic, sterile, pyrogen-free, preservative-free, clear, and colorless solution. Each mL of the solution contains between 740 MBq to 22,200 MBq (20 mCi to 600 mCi) sodium fluoride F 18, at the EOS reference time, in 0.9% aqueous sodium chloride. The pH of the solution is between 4.5 and 8. The solution is presented in 25 mL multiple-dose glass vials with variable total volume and total radioactivity in each vial.

11.2 Physical Characteristics Fluorine F 18 decays by positron (β+) emission and has a half-life of 109.7 minutes. Ninety-seven percent of the decay results in emission of a …

16 HOW SUPPLIED/STORAGE AND HANDLING Sodium Fluoride F 18 Injection is supplied in a multiple-dose Type I glass vial with elastomeric stopper and aluminum crimp seal containing between 370 and 7,400 MBq/mL (10 to 200 mCi/mL ) of no carrier-added sodium fluoride FI8, at the EOS reference time, in aqueous 0.9% sodium chloride solution. The total volume and total radioactivity per vial are variable. Each vial is enclosed in a shielded container of appropriate thickness. The product is available in a 30 mL and 50 mL vial configuration with a variable fill volume. The NDC numbers are: 1 52768-125-30 30 mL Vial 2 52768-125-50 50 mL Vial Storage Store upright in a shielded container at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F). Use the solution within 12 hours of the EOS reference time. Handling Receipt, transfer, handling, possession, or use of this product is subject to the radioactive material regulations and licensing requirements of the U.S. Nuclear Regulatory Commission, Agreement States or Licensing States as appropriate.