FDA Label for Sodium Fluoride F 18

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.

2 Dosage And Administration

2.1 Radiation Safety - Drug Handling

• Wear waterproof gloves and effective shielding when handling Sodium Fluoride F 18 Injection, USP. 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, USP.
• The dose of Sodium Fluoride F 18 Injection, USP 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, USP.
• Encourage the patient to void one-half hour after administration of Sodium Fluoride F 18 Injection, USP 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, USP visually for particulate matter and discoloration before administration, whenever solution and container permit.
• Do not administer Sodium Fluoride F 18 Injection, USP 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, USP 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, USP 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 F 18 Injection, USP [2]. The bone, bone marrow, and urinary bladder are considered target and critical organs.

[1] Data from Nuclear Regulatory Commission Report, Radiation Dose Estimates for Radiopharmaceuticals, NUREG/CR-6345, page 10, 1996.
[2] Data from ICRP publication 53, Radiation Dose to Patients from Radiopharmaceuticals, Ann ICRP, Volume 18, pages 15 and 74, 1987.

2.7 Imaging Guidelines

• Imaging of Sodium Fluoride F 18 Injection, USP can begin 1-2 hours after administration; optimally at 1 hour post administration.
• Encourage the patient to void immediately prior to imaging the fluoride F18 radioactivity in the lumbar spine or bony pelvis.

3 Dosage Forms And Strengths

Multiple-dose vial containing 740-22,200 MBq/mL (20-600 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.

4 Contraindications

None.

5 Warnings And Precautions

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, USP may increase the risk of cancer. Carcinogenic and mutagenic studies with Sodium Fluoride F 18 Injection, USP 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)].

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.

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

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, USP 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, 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 (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-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.

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

Na⁺¹⁸F^-

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 20 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 ¹⁸O-oxygen.

* 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%.

* Calibration time

12 Clinical Pharmacology

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 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

14 Clinical Studies

14.1 Metastatic Bone Disease

The doses used in reported studies ranged from 2.7 mCi to 20 mCi (100 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, USP, focally increased tracer uptake is seen in both osteolytic and osteoblastic bone lesions. Negative PET imaging results with Sodium Fluoride F 18 Injection, USP do not preclude the diagnosis of bone metastases. Also, as benign bone lesions are also detected by Sodium Fluoride F 18 Injection, USP, 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).

15 References

• Stabin, M.G., Stubbs, J. B., and Toohey R. E., Radiation Dose Estimates for Radiopharmaceuticals, U.S. Nuclear Regulatory Commission report NUREG/CR-6345, page 10, 1996.
• Radiation Dose to Patients from Radiopharmaceuticals, ICRP publication 53, Ann ICRP, 18, pages 15 and 74, 1987.
• Kocher, D. C., "Radioactive Decay Data Tables: A Handbook of decay data for application to radiation dosimetry and radiological assessments" DOE/TIC-11026, page 69, 1981.

16 How Supplied/Storage And Handling

Sodium Fluoride F 18 Injection, USP is supplied in a multiple-dose Type 1 glass vial with elastomeric stopper and aluminum crimp seal containing between 740 and 22,200 MBq/mL (20-600 mCi/mL) of no-carrier-added Sodium Fluoride F 18, 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 20 mL vial configuration with a variable fill volume.

The NDC number is: 13267-542-42.

Storage

Store at 25^oC (77^oF) in a shielded container; excursions permitted to 15-30^oC (59-86^oF). 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 Patient Counseling Information

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.

Manufactured and Distributed by:

The Feinstein Institute for Medical Research

Cyclotron/Radiochemistry Facility

350 Community Drive

Manhasset, New York, 11030

Principal Display Panel

Sodium Fluoride F 18 Injection, USP

740 MBq to 22,200 MBq (20 mCi/mL to 600 mCi/mL) at End of Synthesis (EOS)

Diagnostic - For Intravenous Use Only

Sterile, Non-pyrogenic

NDC# 13267-542-42

20 mL Multiple-Dose Vial

CAUTION: RADIOACTIVE MATERIAL RX ONLY

Manufactured by The Feinstein Institute for Medical Research, Manhasset, NY 11030