2.1 Radiation Safety - Drug Handling

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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.

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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.

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Use aseptic technique to maintain sterility during all operations involved in the manipulation and administration of Sodium Fluoride F 18 Injection.

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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.

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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

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To minimize the 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.

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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

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Calculate the necessary volume to administer based on calibration time and dose.

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Inspect Sodium Fluoride F 18 Injection visually for particulate matter and discoloration before administration, whenever solution and container permit.

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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.

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Aseptically withdraw Sodium Fluoride F 18 Injection from its container.

2.4 Recommended Dose for Adults

Administer 300 to 450 MBq (8 to 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 to 148 MBq (0.5 mCi to 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.

2.7 Imaging Guidelines

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Imaging of Sodium Fluoride F 18 Injection can begin 1 to 2 hours after administration; optimally at 1 hour post administration.

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Encourage the patient to void immediately prior to imaging the fluoride F 18 radioactivity in the lumbar spine or bony pelvis.

5.1 Allergic Reactions

As with any injectable drug product, allergic reactions and anaphylaxis may occur. Emergency resuscitation equipment and personnel should be immediately available.

5.2 Radiation Risks

Sodium Fluoride F 18 Injection may increase the risk of cancer. Carcinogenic and mutagenic studies with Sodium Fluoride F 18 injection have not been performed. Use the smallest dose necessary for imaging and ensure safe handling to protect the patient and health care worker [see Dosage and Administration (2.1)].

8.1 Pregnancy

8.3 Nursing Mothers

It is not known whether Sodium Fluoride F 18 Injection 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 or not to administer Sodium Fluoride F 18 Injection, taking into account the importance of the drug to the mother. 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 (10 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 19 MBq to 148 MBq (0.5 mCi to 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.

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[18F] with a molecular weight of 40.99, and has the following chemical structure:

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 370 MBq to 7,400 MBq (10 mCi to 200 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 30 mL and 50 mL multiple- dose glass vials with variable total volume and total radioactivity in each vial.

11.2 Physical Characteristics

Fluoride 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 ke V gamma photons, resulting from the interaction of the emitted positron with an electron (Table 2). Fluorine F 18 atom decays to stable 18O-oxygen.

The specific gamma ray constant for fluoride F 18 is 5.7 R/hr/mCi (1.35 × 10-6 Gy/hr/kBq) at 1 cm. The half-value layer (HVL) for the 511 keV photons is 4 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 radionuc1ide 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 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.

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.

12.2 Pharmacodynamics

Increased fluoride F 18 ion deposition in bone can occur in areas of increased osteogenic activity during growth, infection, malignancy (primary or metastatic) following trauma, or inflammation of bone.

12.3 Pharmacokinetics

After intravenous administration, fluoride F 18 ion is rapidly cleared from the plasma in a biexponential manner. The first phase has a half-life of 0.4 h, and the second phase has a half-life of 2.6 h. Essentially all the fluoride F 18 that is delivered to bone by the blood is retained in the bone. One hour after administration of fluoride, F 18 only about 10% of the injected dose remains in the blood. Fluoride F 18 diffuses through capillaries into bone extracellular fluid space, where it becomes bound by chemisorption at the surface of bone crystals, preferentially at sites of newly mineralizing bone.

Deposition of fluoride F 18 in bone appears to be primarily a function of blood flow to the bone and the efficiency of the bone in extracting the fluoride F 18. Fluoride F 18 does not appear to be bound to serum proteins.

In patients with normal renal function, 20% or more of the fluorine ion is cleared from the body in the urine within the first 2 hours after intravenous administration.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to assess reproductive toxicity, mutagenesis and carcinogenesis potential of Sodium Fluoride F 18 Injection have not been performed.

14.1 Metastatic Bone Disease

The doses used in reported studies ranged from 2.7 mCi to 20 mCi (l00 MBq to 740 MBq), with an average median dose of 10 mCi (370 MBq) and an average mean dose of 9.2 mCi (340 MBq). In PET imaging of bone metastases with Sodium Fluoride F 18 Injection, focally increased tracer uptake is seen in both osteolytic and osteoblastic bone lesions. Negative PET imaging results with Sodium Fluoride F 18 Injection do not preclude the diagnosis of bone metastases. Also, as benign bone lesions are also detected by Sodium Fluoride F 18 Injection, positive PET imaging results cannot replace biopsy to confirm a diagnosis of cancer.

14.2 Other Bone Disorders

The doses used in reported studies ranged from 2.43 mCi to 15 mCi (90 MBq to 555 MBq), with an average median dose of 8.0 mCi (300 MBq) and an average mean dose of 7.6 mCi (280 MBq).

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.

17.1 Pre-Study Hydration

Encourage patients to drink at least 500 mL of water prior to drug administration.

17.2 Post-Study Voiding

To help protect themselves and others in their environment, patients should take the following precautions for 12 hours after injection: whenever possible, use a toilet and flush several times after each use; wash hands thoroughly after each voiding or fecal elimination. If blood, urine or feces soil clothing, wash the clothing separately.