**SODIUM FLUORIDE F 18 INJECTION**

**INVESTIGATOR'S BROCHURE**

Cancer Imaging Program

Division of Cancer Treatment and Diagnosis

National Institutes of Health

6130 Executive Blvd

EPN 6070

Bethesda, MD 20892-7412

Edition: 1

Release Date: August 2008

**INVESTIGATOR'S BROCHURE**

**SODIUM FLUORIDE F 18 INJECTION**

1 TABLE OF CONTENTS 8

LIST OF ABBREVIATIONS 9

[2 SUMMARY 10](#summary)

[3 INTRODUCTION 10](#introduction)

[4 PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES AND FORMULATION
11](#physical-chemical-and-pharmaceutical-properties-and-formulation)

[4.1 Description 11](#description)

[4.2 Physical Properties 11](#physical-properties)

[4.3 Storage 11](#storage)

[5 NONCLINICAL STUDIES 12](#nonclinical-studies)

[6 PREVIOUS HUMAN EXPERIENCE 12](#previous-human-experience)

[6.1 Clinical Pharmacology 12](#clinical-pharmacology)

[6.2 Pharmacokinetics and Metabolism
13](#pharmacokinetics-and-metabolism)

[6.3 Integrated Summaries of Drug Safety and Therapeutic Efficacy
13](#integrated-summaries-of-drug-safety-and-therapeutic-efficacy)

[7 OVERALL DISCUSSION OF DATA AND GUIDE FOR THE INVESTIGATOR
15](#overall-discussion-of-data-and-guide-for-the-investigator)

[8 REFERENCES 16](#references)

LIST OF ABBREVIATIONS

^18^F-NaF Sodium fluoride F 18

CT Computerized axial tomography

EOS End of synthesis

FDA Food and Drug Administration

keV Kiloelectron volt

MBq Megabecquerel

mCi Millicurie

MDP Methylene diphosphonate

mGy Milligray

MRI Magnetic resonance imaging

mSv Millisievert

NaF Sodium fluoride

NCA No carrier added

NDA New Drug Application

PET Positron emission tomography

rem/mCi Estimated absorbed radiation

US United States

USP United States Pharmacopeia

# 2 SUMMARY

Sodium Fluoride F 18 Injection, a positron-emitting radiopharmaceutical
containing no carrier-added (NCA) radioactive fluoride ^18^F, is used
for diagnostic purposes in conjunction with positron emission tomography
(PET) imaging. Sodium Fluoride F 18 Injection is indicated as a bone
imaging agent to define areas of altered osteogenic activity. The
tendency for fluoride ^18^F to accumulate in the vicinity of primary and
metastatic malignancy in bone has proven clinically useful in detection
of such lesions \[*i.e.,* Schirrmeister, 1999, 2001; Hetzel, 2003;
Even-Sapir, 2004\].

# 3 INTRODUCTION

PET is a medical imaging modality that uses a unique type of
radiopharmaceutical drug. PET drugs contain an atom that disintegrates
principally by emission of a positron, which provides dual photons that
are used for imaging, primarily for diagnostic purposes. Most PET drugs
are produced using cyclotrons at locations (PET centers) in close
proximity to the patients to whom the drugs are administered. Each PET
drug is ordinarily injected into the patient within a few minutes or
hours of production.

Sodium Fluoride F 18 Injection is provided as a ready-to-use, isotonic,
sterile, pyrogen-free, clear and colorless solution. Each mL of the
solution contains 10--400 mCi fluoride ^18^F at the end of synthesis
(EOS) reference time in 0.9% aqueous sodium chloride. Fluoride ^18^F
ions decay by positron emission with a half-life of 109.7 minutes. The
drug product complies with the United States Pharmacopeia (USP)
monograph for Sodium Fluoride F 18 Injection, and is manufactured
following procedures that conform to the radiopharmaceuticals for PET
compounding standards (USP \<823\>).

A New Drug Application (NDA) for use of Sodium Fluoride F 18 Injection
as a bone imaging agent to define areas of altered osteogenic activity
was approved by FDA in 1972 (NDA 17-042). The recommended dose of Sodium
Fluoride F 18 Injection for this indication was 0.5 to 2.0 mCi (16.5 to
74.0 MBq), with a maximum recommended dose of 4.0 mCi as an intravenous
injection. The current Sodium Fluoride F 18 Injection NDA-holder stopped
marketing the drug in 1975, around the time that ^99^Tc-labeled
diphosphonate compounds were introduced. Recent advances in PET
technology have led to renewed interest in the use of this compound to
detect bone metastases in cancer patients. Studies have shown sodium
fluoride F 18 (^18^F-NaF) PET and ^18^F-NaF PET/computerized axial
tomography (CT) to be superior to conventional methods, such as
whole-body magnetic resonance imaging (MRI) and ^99m^Tc-methylene
diphosphonate (MDP) bone scans, for accurate and sensitive detection of
bone metastases \[Schirrmeister, 1999, 2001; Hetzel, 2003; Even-Sapir,
2004\]. Evaluations in this setting have used ^18^F-NaF doses ranging
from 7 to 20 mCi. Additional studies directly comparing accuracy,
sensitivity, and cost-effectiveness of available bone imaging
technologies are needed in order to establish the appropriate standard
of care for cancer patients at risk for bone involvement.

# 4 PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES AND FORMULATION

## 4.1 Description

Sodium Fluoride F 18 Injection is provided as a ready-to-use, isotonic,
sterile, pyrogen-free, clear and colorless solution for intravenous
injection. It is produced by particle acceleration in a ^20^N (d,α)
^18^F nuclear reaction from H~2~^18^O. Each mL of the solution contains
between 370 to 14,800 MBq (10--400 mCi) of carrier-free fluoride ^18^F,
at the EOS reference time, in 0.9% aqueous sodium chloride. The pH of
the solution is between 4.5 and 8.0. The solution does not contain any
preservatives. The only known source of nonradioactive fluoride ion
present is that found in the distilled water and saline solutions used
in preparing the product. The drug complies with the USP monograph for
Sodium Fluoride F 18 Injection.

The active ingredient, ^18^F-NaF, has the molecular formula of Na^18^F
with a molecular weight of 40.99, and has the following chemical
structure: Na^+^ 18F^--^.

## 4.2 Physical Properties

Fluoride ^18^F decays by positron (β+) emission and has a half-life of
109.7 minutes. The principal photons used for diagnostic imaging are the
511 keV gamma photons, resulting from the interaction of the emitted
positron with an electron. For use in correcting the physical decay of
this radionuclide, fractions remaining at selected intervals after
calibration are shown in Table 1.

Table 1. Physical Decay Chart for Fluoride ^18^F

  -----------------------------------------------------------------------
  **Time Since Calibration**              **Fraction Remaining**
  --------------------------------------- -------------------------------
  0 minutes                               1.00

  15 minutes                              0.909

  30 minutes                              0.827

  60 minutes                              0.684

  110 minutes                             0.500

  220 minutes                             0.250

  440 minutes                             0.060

  12 hours                                0.011

  24 hours                                0.0001
  -----------------------------------------------------------------------

## 4.3 Storage 

Sodium Fluoride F 18 Injection should be stored upright in a
lead-shielded container at controlled room temperature. Expiration date
and time are provided on the container label. Storage and disposal of
Sodium Fluoride F 18 Injection should be in accordance with the
regulations and general license, or its equivalent, of an Agreement
State or a Licensing State.

# 5 NONCLINICAL STUDIES

Studies with Sodium Fluoride F 18 Injection have not been performed to
evaluate carcinogenic potential, mutagenic potential or effects on
fertility. Animal reproduction studies have not been conducted with
Sodium Fluoride F 18 Injection. In contrast, the toxicology of the
non-radioactive compound is well established due to extensive use in
municipal water fluoridation systems, various dental products, and in a
variety of industrial applications \[Subcommittee on Health Effects of
Ingested Fluoride, 1993; NTP, 1990\]. Approximately 75--90% of the
fluoride ingested each day is absorbed from the alimentary tract
\[Subcommittee on Health Effects of Ingested Fluoride, 1993\]. The *in
vitro* data indicate that the genotoxicity of fluoride is limited
primarily to doses much higher than those to which humans are exposed on
a daily basis. In addition, genotoxic effects are not always observed,
even at high doses, and the preponderance of the genotoxic effects that
have been reported are of the types that probably are of no or
negligible genetic significance \[Subcommittee on Health Effects of
Ingested Fluoride, 1993\]. Adverse effects on reproductive performance
associated with high concentrations of fluoride intake have been
reported in nonclinical studies; the water or food threshold fluoride
concentration associated with these effects is approximately 100 mg/L
(100 mg/kg) \[Subcommittee on Health Effects of Ingested Fluoride,
1993\]. Two-year dosed water studies found equivocal evidence of
carcinogenic activity of sodium fluoride in male F344/N rats, based on
the occurrence of a small number of osteosarcomas in dosed animals
\[NTP, 1990\]. There was no evidence of carcinogenic activity in female
F344/N rats or in male or female B6C3F1 mice receiving sodium fluoride
at concentrations of 25, 100 or 175 ppm for two years \[NTP, 1990\]. The
large number of epidemiological studies in humans showing a lack of
correlation of cancer risk with drinking fluoridated water suggests that
if any link exists, it must be very weak \[Subcommittee on Health
Effects of Ingested Fluoride, 1993\].

The toxicology of Sodium Fluoride F 18 Injection will be the same as
that of the non-radioactive compound, except for the radiation exposure.
However, the amount of fluoride ions in Sodium Fluoride F 18 Injection
at the indicated dose is very low, and provides assurance that toxic
effects will not be observed.

# 6 PREVIOUS HUMAN EXPERIENCE

##  6.1 Clinical Pharmacology

Fluoride ^18^F ions usually accumulate 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.
Increased deposition of fluoride ^18^F around joints can occur in
arthritis or following trauma. Increased deposition has also been
documented in bone around fracture sites, in osteomyelitis, fibrous
dysplasia, spondylitis tuberculosa, Paget's disease, hyperstosis
frontalis interna, myositis ossificans, and in rapidly growing
epiphyses. The tendency for fluoride ^18^F to accumulate in the vicinity
of primary and metastatic malignancy in bone has proven clinically
useful in detection of such lesions

\[FDA, 2000\].

## 6.2 Pharmacokinetics and Metabolism 

Following intravenous administration, Sodium Fluoride F 18 Injection
provides fluoride ^18^F ions that rapidly equilibrate, primarily with
the extracellular fluid space. The fluoride ^18^F ions are then rapidly
cleared by bone deposition and by excretion into the urine \[FDA,
2000\]. Deposition of fluoride ^18^F in bone appears to be primarily a
function of blood flow to the bone and the efficiency of the bone in
extracting the fluoride ions from the blood perfusing the bone
\[Vandyke, 1965\]. Fluoride ^18^F ions do not appear to be bound to
serum proteins . The clearance of fluoride ^18^F from blood is rapid
\[Weber, 1969\]. Fluoride ^18^F is rapidly eliminated via the renal
system. In patients with normal renal function, 20% or more of the
fluoride ^18^F is cleared from the body in urine within the first two
hours after intravenous administration \[Harmer, 1969\]. Subsequently,
small amounts of fluoride ions continue to be excreted in urine, further
diminishing radioactivity of fluoride ions in soft tissues of the body.

## 6.3 Integrated Summaries of Drug Safety and Therapeutic Efficacy

An NDA for use of Sodium Fluoride F 18 Injection as a bone imaging agent
to define areas of altered osteogenic activity was approved by FDA in
1972 (NDA 17-042). The recommended dose of Sodium Fluoride F 18
Injection for this indication was 0.5 to 2.0 mCi (16.5 to 74.0 MBq),
with a maximum recommended dose of 4.0 mCi as an intravenous injection.
According to the PET Safety and Effectiveness Notice, the agency's
findings regarding the already approved NDA for Sodium Fluoride F 18
Injection are the basis for approval of this agent for bone imaging
\[FDA, 2000\].

Fluoride is a normal body constituent. The amount of fluoride ions in
Sodium Fluoride F 18 Injection at the indicated dose is expected to have
minimal effect on normal human physiology. When Sodium Fluoride F 18
Injection was approved for marketing in 1972, no adverse reactions were
noted in over 400 patient studies reported in the medical literature
\[FDA, 2000\]. In a 1999 review of the published literature, publicly
available reference sources and adverse drug reaction reporting systems
indicated that no adverse reactions have been reported for Sodium
Fluoride F 18 Injection \[FDA, 2000\].

The estimated absorbed radiation doses to a human adult (70 kg) from
intravenous administration of Sodium Fluoride F 18 Injection are
provided in Table 2. Bone and bone marrow are considered the target and
critical organs. To minimize the radiation-absorbed dose to the bladder,
adequate hydration should be encouraged to stimulate frequent voiding
during the first few hours after intravenous administration

**Table 2. Estimated Absorbed Radiation Doses after Intravenous
Administration of Sodium Fluoride F 18 Injection in Adult Humans (70 kg)
\[FDA, 2000\]**

# 7 OVERALL DISCUSSION OF DATA AND GUIDE FOR THE INVESTIGATOR

Sodium Fluoride F 18 Injection is a radiopharmaceutical, and should be
handled in accordance with all applicable regulations.
Radiopharmaceuticals should be used only by personnel (*e.g.,*
physicians or radiopharmacists) who are qualified by specific training
in the safe use and handling of radioactive drugs and materials. In the
use of any radiopharmaceutical, care should be taken to ensure minimum
radiation exposure to the patient and all personnel involved in the
procedure.

It is not known whether Sodium Fluoride F 18 Injection can cause fetal
harm when administered to a pregnant woman or can affect reproductive
capacity. Therefore, Sodium Fluoride F 18 Injection should not be
administered to a pregnant woman unless the potential benefit justifies
the potential risk to the fetus. The effects of Sodium Fluoride F 18
Injection on human breast milk are unknown. Because many drugs are
excreted in human milk, caution should be exercised when Sodium Fluoride
F 18 Injection is administered to a nursing woman. The safety and
effectiveness of Sodium Fluoride F 18 Injection has not been established
in pediatric patients, and prudence suggests limiting exposure in
growing children; carefully selected pediatric use has been reported
\[Lim 2007\]. Like other bone imaging agents, Sodium Fluoride F 18
Injection is known to localize in rapidly growing epiphyses in
developing long bones.

Sodium Fluoride F 18 Injection preparations containing particulate
matter or discoloration should not be administered. To maintain
sterility, aseptic technique must be used during all operations involved
in the manipulation and administration of Sodium Fluoride F 18
Injection. The final dose to the patient should be calculated using
proper decay factors from the time of EOS, and measured by a suitable
radioactivity calibration system before administration. (See decay
factors in Table 1.) The patient should be instructed to ingest copious
amounts of fluid immediately prior and subsequent to the administration
of Sodium Fluoride F 18 Injection. The patient should void one-half hour
after the administration of Sodium Fluoride F 18 Injection and as
frequently thereafter as possible. The patient should be instructed to
void immediately prior to imaging the lumbar spine or bony pelvis to
reduce background radioactivity.

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

# 8 REFERENCES

**1.** Even-Sapir E, Metser U, Flusser G, et al. Assessment of malignant
skeletal disease: initial experience with ^18^F-fluoride PET/CT and
comparison between ^18^F-fluoride PET and ^18^F-fluoride PET/CT. *J Nucl
Med.* 2004;45:272--278.

**2.** U.S. Department of Health and Human Services. Food and Drug
Administration. Center for Drug Evaluation and Research (CDER). Guidance
for Industry: PET Drug Applications - Content and Format of NDAs and
ANDAs. March 2000.

**3.** Department of Health and Human Services. Food and Drug
Administration. Positron Emission Tomography Drug Products; Safety and
Effectiveness of Certain PET Drugs for Specific Indications. Notice.
March 10, 2000. *Federal Register.*65:12999-13009.

**4.** Harmer CL, Burns JE, Sams A, Spittle M. The value of fluorine-18
for scanning bone tumours. *Clin Radiol.* 1969;20:204--212.

**5.** Hetzel M, Arslandemir C, Konig HH, et al. F-18 NaF PET for
detection of bone metastases in lung cancer: accuracy,
cost-effectiveness, and impact on patient management. *J Bone Miner
Res.* 2003;18:2206--2214.

**6.** Lim R, Fahey FH, Drubach LA, Connolly LP, Treves ST. Early
experience with fluorine-18 sodium fluoride bone PET in young patients
with back pain. *J Pediatr Orthop.* 2007;27:277--282

**7.** NTP Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS
No. 7681-49-4) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).
*Natl Toxicol Program Tech Rep Ser.* 1990;393:1--448.

**8.** Schirrmeister H, Guhlmann A, Elsner K, et al. Sensitivity in
detecting osseous lesions depends on anatomic localization: planar bone
scintigraphy versus 18F PET. *J Nucl Med.* 1999;40:1623--1629.

**9.** Schirrmeister H, Guhlmann A, Kotzerke J, et al. Early detection
and accurate description of extent of metastatic bone disease in breast
cancer with fluoride ion and positron emission tomography. *J Clin
Oncol.* 1999;17:2381--2389.

**10.** Schirrmeister H, Glatting G, Hetzel J, et al. Prospective
evaluation of the clinical value of planar bone scans, SPECT, and
(18)F-labeled NaF PET in newly diagnosed lung cancer. *J Nucl Med.*
2001;42:1800--1804.

**11.** Subcommittee on Health Effects of Ingested Fluoride. Committee
on Toxicology. Board on Environmental Studies and Toxicology. Commission
on Life Sciences. National Research Council, ed. *Health Effects of
Ingested Fluoride*. Washington, DC: National Academy Press; 1993.

**12.** Vandyke D, Anger HO, Yano Y, Bozzini C. Bone blood flow shown
with F18 and the positron camera. *Am J Physiol.* 1965;209:65--70.

**13.** Weber DA, Greenberg EJ, Dimich A, et al. Kinetics of
radionuclides used for bone studies. *J Nucl Med.* 1969;10:8--17.