**Attachment II**

**Sample Formats ---**

**Labeling for**

**Ammonia N 13 Injection**

**Fludeoxyglucose F 18 Injection \[^18^F\] FDG**

**and**

**Sodium Fluoride F 18 Injection**

This guidance has been prepared by the PET Steering Committee in the
Center for Drug Evaluation and Research (CDER) at the Food and Drug
Administration. This guidance document represents the Agency\'s current
thinking on the content and format of NDAs and ANDAs for certain
positron emission tomography (PET) drug products. It does not create or
confer any rights for or on any person and does not operate to bind FDA
or the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes, regulations, or
both.

**Table of Contents**

Ammonia N 13 Injection
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....
1

Fludeoxyglucose F 18 Injection - \[^18^F\] FDG
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\... 12

Sodium Fluoride F 18 Injection
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....
27

**Ammonia N 13 Injection**

**Diagnostic - For Intravenous Administration**

This guidance has been prepared by the PET Steering Committee in the
Center for Drug Evaluation and Research (CDER) at the Food and Drug
Administration. This guidance document represents the Agency\'s current
thinking on the content and format of NDAs and ANDAs for certain
positron emission tomography (PET) drug products. It does not create or
confer any rights for or on any person and does not operate to bind FDA
or the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes, regulations, or
both.

**Ammonia N 13 Injection**

**Diagnostic - For Intravenous Administration**

# DESCRIPTION

Ammonia N 13 Injection is a positron emitting radiopharmaceutical,
containing radioactive \[^13^N\] ammonia, that is used for diagnostic
purposes in conjunction with positron emission tomography (PET) imaging.
It is administered by intravenous injection.

The active ingredient, \[^13^N\] ammonia, has the molecular formula of
^13^NH~3~ with a molecular weight of 16.02, and has the following
chemical structure:

H

H ^13^N

H

Ammonia N 13 Injection is provided as a ready to use sterile,
pyrogen-free, clear and colorless solution. Each mL of the solution
contains between \_\_\_\_\_\_\_MBq to \_\_\_\_\_MBq \* (\_\_\_mCi to
\_\_\_mCi) \* of \[^13^N\] ammonia, at the end of synthesis (EOS)
reference time, in 0.9% aqueous sodium chloride. The specific activity
of \[^13^N\]ammonia is not less than \_\_\_\_ Ci/mmol,\* and the pH of
the solution is between \_\_\_ to \_\_\_.[^1]^,^[^2]

## Physical Characteristics

Nitrogen N 13 decays by emitting positron to Carbon C 13 (stable) and
has a physical half-life of 9.96 minutes. The principal photons useful
for imaging are the dual 511 keV gamma photons that are produced and
emitted simultaneously in opposite direction when the positron interacts
with an electron (Table 1).

**Table 1. Principal Radiation Emission Data for Nitrogen N 13**

  ------------------------ ----------------------- -----------------------
  **Radiation/Emission**   **% Per                 **Energy**
                           Disintegration**        

  Positron (β+)            100                     1190 keV (Max.)

  Gamma (±)\*\*            200                     511 keV
  ------------------------ ----------------------- -----------------------

\*\* Produced by positron annihilation

The specific gamma ray constant for nitrogen N 13 is 6.0 R/hr/mCi (0.3
Gy/hr/kBq) at 1 cm. The half-value layer (HVL) of lead (Pb) for 511 keV
photons is 4.1 mm. Selected coefficients of attenuation are listed in
Table 2 as a function of lead shield thickness. For example, the use of
52.8 mm thickness of lead will attenuate the external radiation by a
factor of about 1000.

**Table 2. Radiation Attenuation of 511 keV Photons by Lead (Pb)
Shielding**

  ----------------------------------- -----------------------------------
  **Shield Thickness (Pb) mm**        **Coefficient of Attenuation**

  4.1                                 0.5

  8.3                                 0.25

  13.2                                0.1

  26.4                                0.01

  52.8                                0.001
  ----------------------------------- -----------------------------------

Table 3 lists fractions remaining at selected time intervals from the
calibration time. This information may be used to correct for physical
decay of the radionuclide.

**Table 3. Physical Decay Chart for Nitrogen N 13**

  ------------------------ ----------------------------------------------
  **Minutes**              **Fraction Remaining**

  0\*                      1.000

  5                        0.706

  10                       0.499

  15                       0.352

  20                       0.249

  25                       0.176

  30                       0.124
  ------------------------ ----------------------------------------------

> \* Calibration time

# CLINICAL PHARMACOLOGY

## General

Ammonia N 13 Injection is a radiolabeled analog of ammonia that is
rapidly distributed to all organs of the body after intravenous
administration. Optimal PET imaging of the myocardium is generally
achieved between 15 to 20 minutes after administration.

## Pharmacodynamics

Following intravenous injection, ammonia N 13 enters the myocardium
through the coronary arteries. It is extracted from the blood in the
coronary capillaries into the myocardial cells where it is rapidly
metabolized to glutamine N 13 and retained in the cells. The presence of
ammonia N 13 and glutamine N 13 in the myocardium allows for PET imaging
of the myocardium. The PET technique measures myocardial blood flow
based on the assumption of a three-compartmental disposition of
intravenous ammonia

N 13 in the myocardium. In this model, the value of the rate constant,
which represents the delivery of blood to myocardium, and the fraction
of ammonia N 13 extracted into the myocardial cells is a measure of
myocardial blood flow. PET imaging for myocardial blood flow assessment
usually begins at the time of administration of Ammonia N 13 Injection
and continues for about 10 minutes.

## Pharmacokinetics

Following intravenous injection, Ammonia N 13 Injection is cleared
rapidly from the blood with a biologic half-life of about 2.84 minutes
(effective half-life of about 2.21 minutes). In the myocardium, its
biologic half-life has been estimated to be less than 2 minutes
(effective half-life less than 1.67 minutes). In the brain its biologic
half-life is less than 3 seconds.

This mass dose of Ammonia N 13 Injection is very small as compared to
the normal range of ammonia in the blood (0.72 -- 3.30 mg) in a 70 kg
healthy adult man. (See Dosage and Administration section.)

## Distribution

Based on the reviewed literature information, plasma protein binding of
ammonia N 13 or its N 13 metabolites has not been studied.

## Metabolism

Ammonia N 13 undergoes a five-enzyme step metabolism in the liver to
yield urea N 13 (the main circulating metabolite). It is also
metabolized to glutamine N 13 (the main metabolite in tissues) by
glutamine synthase in the skeletal muscles, liver, brain, myocardium,
and other organs. Other metabolites of ammonia N 13 include small
amounts of N 13 amino acid anions (acidic amino acids) in the forms of
glutamate N 13 or aspartate N 13.

## Elimination

Ammonia N 13 is eliminated from the body by urinary excretion mainly as
urea N 13.

## Pharmacokinetics in Special Populations

**Renally Impaired Patients**: Based on the reviewed literature, the
effects of renal impairment on the kinetics of Ammonia N 13 Injection
have not been studied.

**Hepatically Impaired Patients**: Based on the reviewed literature, the
effects of hepatic impairment on the kinetics of Ammonia N 13 Injection
have not been studied.

**Pediatric Patients**: Based on the reviewed literature, the kinetics
of Ammonia N 13 Injection in pediatric patients has not been studied.

## Drug-Drug Interactions

Based on the reviewed literature, the possibility of interactions of
Ammonia N 13 Injection with other drugs taken by patients undergoing PET
imaging has not been studied.

# CLINICAL TRIALS

The efficacy data for Ammonia N 13 Injection in PET was derived from the
evaluation of 14 independent literature reports that assessed a total of
approximately 739 patients. In a key, prospective, blinded image
interpretation study,[^3] the sensitivity and specificity of PET imaging
using Ammonia N 13 Injection in identifying myocardial perfusion
abnormalities in patients presenting for coronary angiography is derived
and shown in Table 4.

+--------------------+------------------------+------------------------+
| **Table 4:         |                        |                        |
| Comparison of      |                        |                        |
| Identified         |                        |                        |
| Coronary Artery    |                        |                        |
| Disease in         |                        |                        |
| Patients Imaged    |                        |                        |
| with Ammonia PET   |                        |                        |
| and Coronary       |                        |                        |
| Angiography**      |                        |                        |
+--------------------+------------------------+------------------------+
| Coronary           | PET Perfusion Defects  |                        |
| Angiography        | ^(a,b,c)^              |                        |
+--------------------+------------------------+------------------------+
|                    | None or Possible       | Probable to Severe     |
|                    |                        |                        |
|                    | (N=68)                 | (N=106)                |
+--------------------+------------------------+------------------------+
| None to Mild       | 66                     | 12                     |
| Stenosis           |                        |                        |
+--------------------+------------------------+------------------------+
| Significant        | 2                      | 94                     |
| Stenosis           |                        |                        |
+--------------------+------------------------+------------------------+
|                    |                        |                        |
+--------------------+------------------------+------------------------+

a PET sensitivity 98% (95% confidence interval: 92.1 -- 99.7%)

b PET specificity 85% (95% confidence interval: 74.7 -- 91.7%)

c PET images are the pooled result of 111 patient image sets obtained
with ammonia N 13 and 82 patient image sets obtained with Rubidium-82.

In this calculation, there were 12 false negatives and 2 false
positives. Thus, further clinical work-up for patients involving
angiography or other tests may be indicated.

Thirteen other reviewed literature reports were supportive of the above
trial's results. None of the reviewed studies evaluated the use of
ammonia in a screening assessment to detect early coronary artery
disease in a healthy, asymptomatic population. The effectiveness and
safety as well as the effect on cardiovascular morbidity and mortality
of Ammonia N 13 Injection in the screening setting is unknown.

# Indications and Usage

Ammonia N 13 Injection is indicated for PET imaging of the myocardium
under rest or pharmacologic stress conditions to evaluate myocardial
perfusion in patients with suspected or existing coronary artery
disease.

# Contraindications

None known.

# 

# Warnings

None known.

# Precautions

## General

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 radionuclides. (See Drug Handling section.) 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 by using the smallest dose of radioactivity consistent with
safety and relative value of diagnostic information.

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

## Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Ammonia N 13 Injection have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.

## Teratogenic Effects: Pregnancy Category C

## 

Animal reproduction studies have not been performed with Ammonia N 13
Injection. It is not known whether Ammonia N 13 Injection can cause
fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Ammonia N 13 Injection should be used in
pregnancy only if the potential benefit justifies the potential risk to
the fetus.

## Nursing Mothers

The effects of Ammonia N 13 Injection on human breast milk are unknown.
Caution should be exercised when Ammonia N 13 Injection is administered
to a nursing woman. Wherever possible, infant formula should be
substituted for breast milk up to 4 to 6 hours after administration.

## Pediatric Use

The safety and effectiveness of Ammonia N 13 Injection have been
established in pediatric patients on the basis of clinical studies in
adults, known metabolism of ammonia, and radiation dosimetry in the
pediatric population. (See Radiation Dosimetry section.)

# 

# Adverse Reactions

Ammonia is a normal body constituent. The amount of ammonia in Ammonia N
13 Injection at the indicated dose has minimal effect on normal human
physiology.

A 1999 review of the published literature, publicly available reference
sources, and adverse drug reaction reporting systems indicated that
adverse reactions have not been reported for Ammonia N 13 Injection.
However, patients should be appropriately monitored for adverse drug
reactions, and such reactions should be reported to FDA, if they occur.

# 

# OVERDOSAGE

Overdoses of Ammonia N 13 Injection have not been reported. (See
Radiation Dosimetry section for related information.)

# DOSAGE AND ADMINISTRATION

The recommended dosages of Ammonia N 13 Injection, as an intravenous
injection, are:

1.  Rest Imaging Studies

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a.  A dose of 10-20[^4] mCi is injected through a catheter inserted into
    a large vein.

b.  After 3 minutes from the initial injection, resting data are
    acquired for 15-20 minutes.

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2.  Stress Imaging Studies

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a.  After 40 minutes from the initial injection (to allow for isotope
    decay), a pharmacologic stress-inducing drug may be administered in
    accordance with its approved labeling.

b.  After 8 minutes from the injection of the pharmacologic stress
    inducing drug, a second dose of Ammonia N 13 Injection 10-20 mCi may
    be injected. Images should be acquired for 15-20 minutes.

## Patient Preparation

To minimize radiation dose to the bladder, the patient should be
hydrated and encouraged to void when the examination is completed and
thereafter as often as possible.

## Drug Handling

Ammonia N 13 Injection, like other parenteral drug products, should be
inspected visually for particulate matter and discoloration before
administration, whenever solution and container permit. Ammonia N 13
Injection preparations containing particulate matter or discoloration
should not be administered. They should be disposed of in a safe manner,
in compliance with applicable regulations.

Aseptic techniques and effective shielding should be employed in
withdrawing doses for administration to patients. Waterproof gloves and
effective shielding should be worn when handling the product.

The contents of each vial are sterile and non-pyrogenic. To maintain
sterility, aseptic technique must be used during all operations involved
in the manipulation and administration of Ammonia N 13 Injection.

As with any other radioactive material, appropriate shielding should be
used to avoid unnecessary radiation exposure to the patient,
occupational workers, and other persons.

Ammonia N 13 Injection, like other radioactive drugs, must be handled
with care and appropriate safety measure should be used to minimize
radiation exposure to clinical personnel. Care should be taken to
minimize exposure to the patient consistent with proper patient
management. 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.

# 

## Radiation Dosimetry

The converted radiation absorbed doses in rem/mCi are shown in Table 5.
Based on these data, the absorbed doses per unit of activity in selected
organs are higher in pediatric patients under 10 years of age. These
organs are the heart, bladder wall, red marrow, testes, and ovaries.
Specifically, the absorbed radiation doses per unit activity of Ammonia
N 13 Injection for adults and pediatric patients 15 years old or older
(5 years old or older for the brain) are similar. However, for pediatric
patients under 10 years of age ( under 1 year old for the brain), the
absorbed radiation doses per unit activity appear to be higher than
adult values. These data also indicate that for each of the age groups
evaluated (i.e., pediatric patients from 1, 5, 10, and 15 year(s) old as
well as adults), the organ with the highest radiation exposure is the
urinary bladder wall.

  -------------- ----------- ----------- ----------- ----------- ----------
  **Table 5: N                                                   
  13: Absorbed                                                   
  Radiation Dose                                                 
  Per Unit                                                       
  Activity                                                       
  (rem/mCi) for                                                  
  Adults and                                                     
  Pediatric                                                      
  Groups 1, 5,                                                   
  10, and 15                                                     
  Years Old**                                                    

  **Organ**      **Adult**   **15 year   **10 year   **5 year    **1 year
                             old**       old**       old**       old**

  Adrenals       0.0085      0.0096      0.016       0.025       0.048

  Bladder wall   0.030       0.037       0.056       0.089       0.17

  Bone surfaces  0.0059      0.0070      0.011       0.019       0.037

  Brain          0.016       0.016       0.017       0.019       0.027

  Breast         0.0067      0.0067      0.010       0.017       0.033

  Stomach wall   0.0063      0.0078      0.012       0.019       0.037

  Small          0.0067      0.0081      0.013       0.021       0.041
  intestine                                                      

  \*ULI          0.0067      0.0078      0.013       0.021       0.037

  \*\*LLI        0.0070      0.0078      0.013       0.020       0.037

  Heart          0.0078      0.0096      0.015       0.023       0.041

  Kidneys        0.017       0.021       0.031       0.048       0.089

  Liver          0.015       0.018       0.029       0.044       0.085

  Lungs          0.0093      0.011       0.018       0.029       0.056

  Ovaries        0.0063      0.0085      0.014       0.021       0.041

  Pancreas       0.0070      0.0085      0.014       0.021       0.041

  Red marrow     0.0063      0.0078      0.012       0.020       0.037

  Spleen         0.0093      0.011       0.019       0.030       0.056

  Testes         0.0067      0.0070      0.011       0.018       0.035

  Thyroid        0.0063      0.0081      0.013       0.021       0.041

  Uterus         0.0070      0.0089      0.014       0.023       0.041

  Other tissues  0.0059      0.0070      0.011       0.018       0.035
  -------------- ----------- ----------- ----------- ----------- ----------

\*Upper large intestine, \*\*Lower large intestine

# HOW SUPPLIED

Ammonia N 13 Injection is packaged in \_\_\_mL [^5] single dose/multiple
dose glass vial containing between \_\_\_MBq to \_\_\_MBq \* (\_\_\_mCi
to \_\_\_mCi) \* of \[^13^N\]ammonia, at the end of synthesis (EOS)
reference time, in approximately \_\_\_mL \* volume.

## Storage

Store at \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ \*

Use the solution within \_\_\_\_ minutes [^6] of the End of Synthesis
(EOS) calibration time.

## Expiration Date and Time

The expiration date and time are provided on the container label.

**Caution: Rx ONLY**

Manufactured by: \*

Distributed by: \*

Facility Name \*

Complete Address

City, State and Zip Code [^7]

# LABELING

# IMMEDIATE CONTAINER

# VIAL/LEAD PIG

## Ammonia N 13 Injection

## Diagnostic-For Intravenous Administration

Lot#\_\_\_\_\_\_\_\_\_\_\_\_\_\_
ExpirationDate/Time:\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_/\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
\*

(\_\_\_ minutes after EOS)

Calibration: Date \* Time \* (EOS)

Activity Concentration: mCi\* in mL\*@ EOS

Each mL contains \_\_\_\_\_ - \_\_\_\_\_MBq \* (\_\_\_\_ - \_\_\_ mCi)
\* of \[^13^N\] ammonia @ EOS and 9 mg of sodium chloride. Store upright
in a shielded container at controlled room temperature. Do not use if
cloudy or contains particulate matter. \[^13^N\] Half-life = 9.96 min.
Calculate correct dosage from date and time of calibration. Manufactured
by \_\_\_\_\_\_\_\_.[^8] (radioactivity caution statement and symbol)

EOS = End of Synthesis

Caution: **Rx Only.**

**Fludeoxyglucose F 18 Injection - \[^18^F\] FDG**

**Diagnostic --- For Intravenous Administration**

This guidance has been prepared by the PET Steering Committee in the
Center for Drug Evaluation and Research (CDER) at the Food and Drug
Administration. This guidance document represents the Agency\'s current
thinking on the content and format of NDAs and ANDAs for certain
positron emission tomography (PET) drug products. It does not create or
confer any rights for or on any person and does not operate to bind FDA
or the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes, regulations, or
both.

**Fludeoxyglucose F 18 Injection - \[^18^F\] FDG**

**Diagnostic - For Intravenous Administration**

# DESCRIPTION

Fludeoxyglucose F 18 Injection is a positron emitting
radiopharmaceutical containing no-carrier added radioactive
2-deoxy-2-\[^18^F\]fluoro-D-g1ucose, which is used for diagnostic
purposes in conjunction with Positron Emission Tomography (PET). It is
administered by intravenous injection.

The active ingredient 2-deoxy-2-\[^18^F\]fluoro-D-g1ucose, abbreviated
\[^18^F\] FDG, has a molecular formula of C~8~H~11~^18^FO~5~ with a
molecular weight of 181.26 daltons, and has the following chemical
structure:

![](media/image1.png){width="3.754861111111111in"
height="2.204861111111111in"}

Fludeoxyglucose F 18 Injection is provided as a ready to use isotonic,
sterile, pyrogen free, clear, colorless solution. Each mL contains
between \_\_\_\_\_ to \_\_\_\_\_ MBq \* (\_\_ -- \_\_ mCi) [^9] of
2-deoxy-2-\[^18^F\]fluoro-D glucose at the end of synthesis (EOS), and 9
mg of sodium chloride. The pH of the solution is between \_\_\_ to
\_\_\_ .\*^,^[^10] The solution is packaged in a multiple-dose glass
vial and does not contain any preservative.

## Physical Characteristics

Fluorine F 18 decays by positron (β+) emission and has a half-life of
109.7 minutes. 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 1).

**Table 1.** **Principal Emission Data for Fluorine 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

> From: Kocher, D.C. \"Radioactive Decay Tables\" DOE/TIC-i 1026, 89
> (1981).

## External Radiation

The specific gamma ray constant for fluorine F 18 is 6.0 R/hr/mCi (0.3
Gy/hr/kB) at 1cm. 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 2. 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 2.** **Radiation Attenuation of 511 keV Photons by Lead (Pb)
Shielding**

  ----------------------------------- -----------------------------------
  **Shield Thickness (Pb) mm**        **Coefficient of Attenuation**

  0                                   0.00

  4.1                                 0.50

  8.3                                 0.25

  13.2                                0.10

  26.4                                0.01

  52.8                                0.001
  ----------------------------------- -----------------------------------

For use in correcting for physical decay of this radionuclide, the
fractions remaining at selected intervals after calibration are shown in
Table 3.

**Table 3. Physical Decay Chart for Fluorine F 18**

  ----------------------- -----------------------------------------------
  **Minutes**             **Fraction Remaining**

  0                       1.00

  15                      0.909

  30                      0.826

  60                      0.683

  110                     0.500

  220                     0.250

  440                     0.060
  ----------------------- -----------------------------------------------

> \*Calibration Time

# CLINICAL PHARMACOLOGY

## General

Fludeoxyglucose F 18 Injection is a radiolabeled analog of glucose that
is rapidly distributed to all organs of the body after intravenous
administration. After background clearance of Fludeoxyglucose F 18
Injection, optimal PET imaging is generally achieved between 30 to 40
minutes after administration.

## Pharmacodynamics

Fludeoxyglucose F 18 Injection 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 can not 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.

[]{.mark}

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.

In cancer, the cells are generally characterized by enhanced glucose
metabolism partially due to (1) an increase in the activity of glucose
transporters, (2) an increased rate of phosphorylation activity, (3) a
reduction of phosphatase activity or, (4) a dynamic alteration in the
balance among all these processes. However, glucose metabolism of cancer
as reflected by fludeoxyglucose F 18 accumulation shows considerable
variability. Depending on tumor type, stage, and location,
fludeoxyglucose F 18 accumulation may be increased, normal, or
decreased. Also, inflammatory cells can have the same variability of
uptake of fludeoxyglucose F 18.

In the heart under normal aerobic conditions, the myocardium meets the
bulk of its energy requirements by oxidizing free fatty acids. Most of
the exogenous glucose taken up by the myocyte is converted into
glycogen. However, under ischemic conditions, the oxidation of free
fatty acids decreases, exogenous glucose becomes the preferred
myocardial substrate, glycolysis is stimulated, and glucose taken up by
the myocyte is metabolized immediately instead of being converted into
glycogen. Under these conditions, phosphorylated fludeoxyglucose F 18
accumulates in the myocyte and can be detected with PET imaging.

Normally, the brain relies on anaerobic metabolism. In epilepsy, the
glucose metabolism varies. Generally during a seizure, glucose
metabolism increases. Interictally, the seizure focus tends to be
hypometabolic.

## Pharmacokinetics

In four healthy male volunteers, receiving an intravenous administration
of 30 seconds in duration, the arterial blood level profile for
fludeoxyglucose F 18 was described as a triexponential decay curve. The
effective half-life ranges of the three phases were 0.2-0.3 minutes,
10-13 minutes with a mean and standard deviation (STD) of 11.6
[+]{.underline} 1.1 min, and 80-95 minutes with a mean and STD of 88 ± 4
min.

Within 33 minutes, a mean of 3.9% of the administrated radioactive dose
was measured in the urine. The amount of radiation exposure of the
urinary bladder at 2 hours postadministration suggests that 20.6% (mean)
of the radioactive dose was present in the bladder. (See the Metabolism
section for additional clearance times.)

## Distribution 

The extent of binding of fludeoxyglucose F 18 to plasma proteins is not
known.

## Metabolism

Fludeoxyglucose F 18 Injection is transported into cells and
phosphorylated to \[^18^F\]-FDG-6-phosphate at a rate proportional to
the rate of glucose utilization within that tissue.
\[^18^F\]FDG-6-phosphate presumably is metabolized to
2-deoxy-2-\[^18^F\]fluoro-6-phospho-D-mannose
(\[^18^F\]FDM-6-phosphate).

Fludeoxyglucose F 18 Injection may contain several impurities (e.g.,
2-deoxy-2-chloro-D-glucose (ClDG)). Biodistribution and metabolism of
C1DG are presumed to be similar to fludeoxyglucose F 18 and would be
expected to result in intracellular formation of
2-deoxy-2-chloro-6-phospho-D-glucose (C1DG-6-phosphate) and
2-deoxy-2-chloro-6-phospho-D-mannose (ClDM-6-phosphate). The
phosphorylated deoxyglucose compounds are dephosphorylated and the
resulting compounds (FDG, FDM, C1DG, and ClDM) presumably leave cells by
passive diffusion.

Fludeoxyglucose F 18 and related compounds are cleared from non-cardiac
tissues within 3 to 24 hours after administration. Clearance from the
cardiac tissue may require more than 96 hours. Fludeoxyglucose F 18 that
is not involved in glucose metabolism in any tissue is excreted
unchanged in the urine.

## Elimination 

Fludeoxyglucose F 18 is cleared from most tissues within 24 hours and
can be eliminated from the body unchanged in the urine. Three
elimination phases have been identified in the reviewed literature. In
one study, there is an early elimination phase ("alpha": half-life of
0.2-0.3 minutes) and two late phases ("beta": half life of 11.6 ±1.1
minutes and "gamma": half life of 88± 4 minutes). Another study reported
a "beta" phase (half life of 4.2 ±1.1 minutes) and "gamma" phase (half
life of 50.1 ±14.6 minutes). Within 33 minutes, a mean of 3.9% of the
injected dose was measured in the urine of normal subjects. Within 2
hours of administration, a mean of 20.6% of the injected dose was found
in the bladder.

## 

## Pharmacokinetics in Special Populations

Extensive dose range and dose adjustment studies with this drug product
in normal and special populations have not been completed. In pediatric
patients with epilepsy, doses given have been as low as 2.6 mCi.

The pharmacokinetics of Fludeoxyglucose F 18 Injection in renally
impaired patients have not been characterized. Fludeoxyglucose F 18 is
eliminated through the renal system. Care should be taken to prevent
excessive and unnecessary radiation exposure to this organ system and
adjacent tissues.

The effects of fasting, varying blood sugar levels, conditions of
glucose intolerance, and diabetes mellitus on fludeoxyglucose F 18
distribution in humans have not been ascertained. Diabetic patients may
need stabilization of blood glucose levels on the day before and on the
day of the Fludeoxyglucose F 18 Injection study.

## Drug-Drug Interactions 

Drug-drug interactions with Fludeoxyglucose F 18 Injection have not been
evaluated.

# CLINICAL TRIALS 

**Oncology:** [^11] The efficacy of Fludeoxyglucose F 18 Injection in
positron emission tomography cancer imaging was demonstrated in 16
independent literature reports. These studies prospectively evaluated
the sensitivity and specificity of fludeoxyglucose F 18 for detecting
malignancies. All these studies had at least 50 patients and used
pathology as a standard of truth to compare the results of PET imaging
with Fludeoxyglucose F 18 Injection. The studies encompassed a variety
of cancers: non-small cell lung cancer, colo-rectal, pancreatic, breast,
thyroid, melanoma, Hodgkin's and non-Hodgkin's lymphoma, and various
types of metastatic cancers to lung, liver, bone, and axillary nodes.
The doses in the studies ranged from 200 MBq to 740 MBq with a median
and mean dose of 370 MBq.

In these studies the patients had a clinical reason for the evaluation
of malignancy (e.g., the patients had an abnormality identified by a
prior test and were seeking a diagnosis, or the patients had an existing
diagnosis of cancer and were having further work-up or monitoring). None
of these studies evaluated the use of Fludeoxyglucose F 18 Injection in
routine population screening in which healthy, asymptomatic people are
tested for purposes of cancer early detection. The efficacy of
fludeoxyglucose F 18 PET imaging in cancer screening, including its
ability to decrease cause-specific mortality, is unknown.

In PET imaging with Fludeoxyglucose F 18 Injection, sensitivity is
restricted by the biologic variability of cancer glucose utilization
found in individual patients, with different cancers (see Clinical
Pharmacology and Pharmacodynamic sections). In the reviewed studies, the
sensitivity and specificity varied with the type of cancer, size of
cancer, and other clinical parameters. Also, there were false negatives
and false positives. Negative PET imaging results with Fludeoxyglucose F
18 Injection do not preclude the diagnosis of cancer and further work-up
is indicated. Also, positive PET imaging results with Fludeoxyglucose F
18 Injection can not replace biopsy to confirm a diagnosis of cancer.
There are non-malignant conditions such as fungal infections,
inflammatory processes, and benign tumors that had patterns of increased
glucose metabolism that give rise to false-positive examinations.

## []{.mark}

**Cardiology:** [^12] The efficacy of Fludeoxyglucose F 18 Injection for
cardiac use was demonstrated in ten independent literature reports,
which, in general, shared the characteristics summarized below. The
studies were prospective and enrolled patients with coronary artery
disease and chronic left ventricular systolic dysfunction of a mild to
moderate degree. The patients were scheduled to undergo coronary
revascularization with either coronary artery bypass surgery or
angioplasty. Before revascularization, patients underwent PET imaging
with Fludeoxyglucose F 18 Injection and perfusion imaging with other
diagnostic radiopharmaceuticals. Doses of Fludeoxyglucose F 18 Injection
ranged from 74-370 MBq (2-10 mCi). Segmental, left ventricular,
wall-motion assessments of asynergic areas made before revascularization
were compared to those made after successful revascularization to
identify myocardial segments with functional recovery. Segmental wall
motion assessments were made blinded to the results of
metabolic/perfusion imaging, and PET image analyses were quantitative.

Left ventricular myocardial segments were predicted to have reversible
loss of systolic function if they showed fludeoxyglucose F 18
accumulation and reduced perfusion (i.e., flow-metabolism mismatch).
Conversely, myocardial segments were predicted to have irreversible loss
of systolic function if they showed concordant reductions in both
fludeoxyglucose F 18 accumulation and

perfusion (i.e., matched defects). Diagnostic performance measures such
as sensitivity, specificity, positive predictive value, and negative
predictive value were calculated. None of the studies prospectively
determined the degree to which mismatch, or the location of mismatch,

is associated with improvements in global ventricular function, clinical
symptoms, exercise tolerance, or survival.

Findings of flow-metabolism mismatch in a myocardial segment suggest
that successful revascularization will restore myocardial function in
that segment. However, false-positive tests

occur regularly, and the decision to have a patient undergo
revascularization should not be based on PET findings alone. Similarly,
findings of a matched defect in a myocardial segment suggest that
myocardial function will not recover in that segment, even if it is
successfully

revascularized. However, false-negative tests occur regularly, and the
decision to recommend against coronary revascularization, or to
recommend a cardiac transplant, should not be based on PET findings
alone. The reversibility of segmental dysfunction as predicted with
fludeoxyglucose F 18 PET imaging depends on successful coronary
revascularization. Therefore, in patients with a low likelihood of
successful revascularization, the diagnostic usefulness of PET imaging
with Fludeoxyglucose F 18 Injection is limited.

**Epilepsy:**[^13] In a prospective, open label trial, Fludeoxyglucose F
18 Injection was evaluated in 86 patients with epilepsy. Each patient
received a dose of Fludeoxyglucose F 18 Injection in the range of
185-370 MBq (5-10 mCi). Demographic characteristics of race and gender
are not available. The mean age was 16.4 years (range: 4 months - 58
years; of these, 42 patients were \< 12 years and 16 patients were \<2
years old). Patients had a known diagnosis of complex partial epilepsy
and were under evaluation as surgical candidates for treatment of their
seizure disorder. Seizure foci had been previously identified on ictal
EEGs and sphenoidal EEGs. In 16% (14/87) of patients, the
pre-Fludeoxyglucose F 18 Injection findings were confirmed by
fludeoxyglucose F 18; 34% (30/87) of patients, images of Fludeoxyglucose
F 18 Injection provided new findings. In 32% (27/87), imaging with
Fludeoxyglucose F 18 Injection was not definitive. The influence of
these findings on surgical outcome, medical management, or behavior is
not known.

Several other studies comparing imaging with Fludeoxyglucose F 18
Injection results to subsphenoidal EEG, MRI and/or surgical findings
supported the concept that the degree of hypometabolism corresponds to
areas of confirmed epileptogenic foci.

The safety and effectiveness of Fludeoxyglucose F 18 Injection to
distinguish idiopathic epileptogenic foci from tumors or other brain
lesions that may cause seizures have not been established.

# INDICATIONS AND USAGE

Fludeoxyglucose F 18 Injection is indicated in positron emission
tomography (PET) imaging 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 diagnoses of cancer.

Fludeoxyglucose F 18 Injection is indicated in positron emission
tomography (PET) imaging in patients with coronary artery disease and
left ventricular dysfunction, when used together with myocardial
perfusion imaging, for the identification of left ventricular myocardium
with residual glucose metabolism and reversible loss of systolic
function.

Fludeoxyglucose F 18 Injection is indicated in positron emission
tomography (PET) imaging in patients for the identification of regions
of abnormal glucose metabolism associated with foci of epileptic
seizures.

# 

# CONTRAINDICATIONS

None known

# 

# WARNINGS

None known

# 

# PRECAUTIONS

## General

Use in patients with diabetes or hyperglycemia has not been well
studied. It is recommended that patients be normoglycemic when
undergoing PET imaging with Fludeoxyglucose F 18 Injection.

## 

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 radionuclides. (See Drug Handling section.) 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 by using the smallest dose of radioactivity consistent with
safety and relative value of diagnostic information.

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

## Information for Patients

To minimize radiation absorbed dose to the bladder, adequate hydration
should be encouraged to permit frequent voiding during the first few
hours after intravenous administration of Fludeoxyglucose F 18
Injection. This may be achieved by having patients drink at least an 8
oz glass of water prior to drug administration. To help protect
themselves and others in their environment, patients should take the
following precautions for 12 hours after injection: whenever possible a
toilet should be used and should be flushed several times after each use
and

hands should be washed thoroughly after each voiding or fecal
elimination. If blood, urine or feces soil clothing, the clothing should
be washed separately.

## Diabetic Patients

Transport of fludeoxyglucose F 18 into cells may be affected by fasting
or by blood glucose changes associated with diabetes mellitus. Diabetic
patients may need stabilization of blood glucose levels on the day
before and on the day of administration of Fludeoxyglucose F 18
Injection.

## Carcinogenesis, Mutagenesis, Impairment or Fertility 

## 

Studies with Fludeoxyglucose F 18 Injection have not been performed to
evaluate carcinogenic potential, mutagenic potential or effects on
fertility.

## Teratogenic Effects: Pregnancy Category C

Animal reproduction studies have not been conducted with Fludeoxyglucose
F 18 Injection. It is not known whether Fludeoxyglucose F 18 Injection
can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Therefore, Fludeoxyglucose F 18 Injection should
not be administered to a pregnant woman unless the potential benefit
justifies the

potential risk to the fetus.

## Nursing Mothers

The effects of Fludeoxyglucose F 18 Injection on human breast milk are
unknown. Because many drugs are excreted in human milk, caution should
be exercised when Fludeoxyglucose F 18 Injection is administered to a
nursing woman.

## 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 pediatrics, the recommended dose is
2.6 mCi. The optimal dose adjustment on the basis of body size or weight
has not been determined. (See Radiation Dosimetry section.)

The safety and effectiveness of Fludeoxyglucose F 18 Injection for the
evaluation of malignancy or for the identification of left ventricular
myocardium with reversible loss of systolic function in pediatric
patients below the age of 16 years have not been established. (See
Clinical Trials and Radiation Dosimetry section.)

# ADVERSE REACTIONS

The Fludeoxyglucose F 18 Injection safety database for epilepsy included
of 374 patients. Of these, 245 were male and 105 were female. For 24
patients, gender was not specified. The mean age was 47.8 years (range
under 2 to over 65 years). Eighteen patients were between the age of 0
and 2 years; 42 patients were between the ages of 2 and 21 years; 213
patients were between 21 and 65 years; 98 patients were older than 65
years; and the ages of 3 male patients were not specified. A racial
distribution is not available. In this database, adverse drug reactions
that required medical intervention were not reported. In a small, 42
patient subset of the 374 patients studied, 4 patients had transient
hypotension, 6 had hypo- or hyperglycemia and 3 had transient increases
in alkaline phosphatase.

In a 1999 review of the published literature, publicly available
reference sources, and adverse drug reaction reporting systems indicated
that adverse reactions have not been reported for Fludeoxyglucose F 18
Injection. However, patients should be appropriately monitored for
adverse drug reactions and should be reported to FDA, if they occur.

# OVERDOSAGE

Overdoses of Fludeoxyglucose F 18 Injection have not been reported. (See
Radiation Dosimetry section for related information.)

# DOSAGE AND ADMINISTRATION

The recommended dose of Fludeoxyglucose F 18 Injection for an adult (70
kg) is 185-370 MBq (5-10 mCi), as an intravenous injection for studies
of malignancy, cardiology, and epilepsy.

In general, Fludeoxyglucose F 18 Injection should be administered after
patients have fasted for 4-6 hours. For cardiac use, Fludeoxyglucose F
18 Injection may be administered either to patients who have fasted or
to patients who have received a glucose load. (See Patient Preparation
section.)

The optimum rates of administration and upper safe dose for
Fludeoxyglucose F 18 Injection have not been established. The time
interval between doses of Fludeoxyglucose F 18 Injection should be long
enough to allow substantial decay (physical and biological) of previous
administrations.

The final dose for the patient should be calculated using proper decay
factors from the time of the end of synthesis (EOS) and measured by a
suitable radioactivity calibration system before

administration. (See decay factors in Table 3.)

## Patient Preparation

Blood glucose levels should be stabilized before Fludeoxyglucose F 18
Injection is administered. In non-diabetic patients this may be
accomplished by fasting 4-6 hours before Fludeoxyglucose F 18 Injection.
Diabetic patients may need stabilization of blood glucose on the day
preceding and on the day of administration of Fludeoxyglucose F 18
Injection.

For cardiac imaging, administration of Fludeoxyglucose F 18 Injection to
fasting patients limits

the accumulation of fludeoxyglucose F 18 to ischemic myocardium. This
may make localization of the ischemic region difficult because the
surrounding myocardium will not be well visualized. Conversely,
administration of Fludeoxyglucose F 18 Injection to patients who have
received a glucose load (e.g., 50-75 grams, 1-2 hours before
administration of Fludeoxyglucose F 18 Injection) allows the
surrounding, non-ischemic myocardium to be seen and facilitates
localization of ischemic areas.

## Imaging 

Optimally, it is recommended that positron emission tomography (PET)
imaging be initiated within 40 minutes of administration of
Fludeoxyglucose F 18 Injection.

Static emission scans are acquired 30-100 minutes after the time of
injection.

# 

## Drug Handling

Fludeoxyglucose F 18 Injection, like other parenteral drug products,
should be inspected visually for particulate matter and discoloration
before administration, whenever solution and container permit.
Fludeoxyglucose F 18 Injection preparations containing particulate
matter or discoloration should not be administered. They should be
disposed of in a safe manner, in compliance with applicable regulations.

Aseptic techniques and effective shielding should be employed in
withdrawing doses for administration to patients. Waterproof gloves and
effective shielding should be worn when handling the product.

The contents of each vial are sterile and non-pyrogenic. To maintain
sterility, aseptic technique must be used during all operations involved
in the manipulation and administration of Fludeoxyglucose F 18
Injection.

The current reference listed drug (RLD) states that Fludeoxyglucose F 18
Injection should be used within 8 hours of the end of synthesis (EOS).

As with any other radioactive material, appropriate shielding should be
used to avoid unnecessary radiation exposure to the patient,
occupational workers, and other persons.

Fludeoxyglucose F 18 Injection, like other radioactive drugs, must be
handled with care and appropriate safety measures should be used to
minimize radiation exposure to clinical personnel. Care should be taken
to minimize exposure to the patient consistent with proper patient
management. 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.

## 

## Radiation Dosimetry

The estimated absorbed radiation doses (rem/mCi) to a 1-year old (9.8
kg), 5-year old (19 kg), 10-year old (32 kg), 15-year old (57 kg), and
adult human (70 kg) from intravenous injection of Fludeoxyglucose F 18
Injection are shown in Table 4. These estimates were calculated based on
human[^14] data and using the data published by the International
Commission on Radiological

Protection[^15] for Fludeoxyglucose F 18 Injection. The dosimetry data
obtained and presented in this table 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
understood to be 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
(i.e., newborn, 1, 5, 10, 15 year(s) and adults) are the urinary
bladder, heart, pancreas, spleen, and lungs. The absolute values for
absorbed radiation in each of these organs vary in each of the age
groups.

**Table 4. Estimated Absorbed Radiation Doses (rem/mCi) After
Intravenous Administration of 2-deoxy-2-\[18F\]fluoro-D-glucose,
Fludeoxyglucose F 18 Injection.**

+--------------+---------+--------+--------+-------+--------+------+
| **Organ**    | **Newbo | **     | **     | **10  | **1    | **Ad |
|              | rn^1^** | 1-year | 5-year | -year | 5-year | ult^ |
|              |         | ol     | ol     | old   | ol     | 1^** |
|              | **(3.4  | d^1^** | d^1^** | ^1^** | d^1^** |      |
|              | kg)**   |        |        |       |        | *    |
|              |         | **(9.8 | **(19  | **(32 | **(57  | *(70 |
|              |         | kg)**  | kg)**  | kg)** | kg)**  | k    |
|              |         |        |        |       |        | g)** |
+--------------+---------+--------+--------+-------+--------+------+
| Bladder      | 4.3     | 1.7    | 0.93   | 0.60  | 0.40   | 0.32 |
| wall^2^      |         |        |        |       |        |      |
+--------------+---------+--------+--------+-------+--------+------+
| Heart wall   | 2.4     | 1.2    | 0.70   | 0.44  | 0.29   | 0.22 |
+--------------+---------+--------+--------+-------+--------+------+
| Pancreas     | 2.2     | 0.68   | 0.33   | 0.25  | 0.13   | 0    |
|              |         |        |        |       |        | .096 |
+--------------+---------+--------+--------+-------+--------+------+
| Spleen       | 2.2     | 0.84   | 0.46   | 0.29  | 0.19   | 0.14 |
+--------------+---------+--------+--------+-------+--------+------+
| Lungs        | 0.96    | 0.38   | 0.20   | 0.13  | 0.092  | 0    |
|              |         |        |        |       |        | .064 |
+--------------+---------+--------+--------+-------+--------+------+
| Kidneys      | 0.81    | 0.34   | 0.19   | 0.13  | 0.089  | 0    |
|              |         |        |        |       |        | .074 |
+--------------+---------+--------+--------+-------+--------+------+
| Ovaries      | 0.80    | 0.8    | 0.19   | 0.11  | 0.058  | 0    |
|              |         |        |        |       |        | .053 |
+--------------+---------+--------+--------+-------+--------+------+
| Uterus       | 0.79    | 0.35   | 0.19   | 0.12  | 0.076  | 0    |
|              |         |        |        |       |        | .062 |
+--------------+---------+--------+--------+-------+--------+------+
| LLI wall \*  | 0.69    | 0.28   | 0.15   | 0.097 | 0.060  | 0    |
|              |         |        |        |       |        | .051 |
+--------------+---------+--------+--------+-------+--------+------+
| Liver        | 0.69    | 0.31   | 0.17   | 0.11  | 0.076  | 0    |
|              |         |        |        |       |        | .058 |
+--------------+---------+--------+--------+-------+--------+------+
| Gallbladder  | 0.69    | 0.26   | 0.14   | 0.093 | 0.059  | 0    |
| wall         |         |        |        |       |        | .049 |
+--------------+---------+--------+--------+-------+--------+------+
| Sm intestine | 0.68    | 0.29   | 0.15   | 0.096 | 0.060  | 0    |
|              |         |        |        |       |        | .047 |
+--------------+---------+--------+--------+-------+--------+------+
| ULI wall     | 0.67    | 0.27   | 0.15   | 0.090 | 0.057  | 0    |
| \*\*         |         |        |        |       |        | .046 |
+--------------+---------+--------+--------+-------+--------+------+
| Stomach wall | 0.65    | 0.27   | 0.14   | 0.089 | 0.057  | 0    |
|              |         |        |        |       |        | .047 |
+--------------+---------+--------+--------+-------+--------+------+
| Adrenals     | 0.65    | 0.28   | 0.15   | 0.095 | 0.061  | 0    |
|              |         |        |        |       |        | .048 |
+--------------+---------+--------+--------+-------+--------+------+
| Testes       | 0.64    | 0.27   | 0.14   | 0.085 | 0.052  | 0    |
|              |         |        |        |       |        | .041 |
+--------------+---------+--------+--------+-------+--------+------+
| Red marrow   | 0.62    | 0.26   | 0.14   | 0.089 | 0.057  | 0    |
|              |         |        |        |       |        | .047 |
+--------------+---------+--------+--------+-------+--------+------+
| Thymus       | 0.61    | 0.26   | 0.14   | 0.086 | 0.056  | 0    |
|              |         |        |        |       |        | .044 |
+--------------+---------+--------+--------+-------+--------+------+
| Thyroid      | 0.61    | 0.26   | 0.13   | 0.080 | 0.049  | 0    |
|              |         |        |        |       |        | .039 |
+--------------+---------+--------+--------+-------+--------+------+
| Muscle       | 0.58    | 0.25   | 0.13   | 0.078 | 0.049  | 0    |
|              |         |        |        |       |        | .039 |
+--------------+---------+--------+--------+-------+--------+------+
| Bone         | 0.57    | 0.24   | 0.12   | 0.079 | 0.052  | 0    |
| surfaces     |         |        |        |       |        | .041 |
+--------------+---------+--------+--------+-------+--------+------+
| Breast       | 0.54    | 0.22   | 0.11   | 0.068 | 0.043  | 0    |
|              |         |        |        |       |        | .034 |
+--------------+---------+--------+--------+-------+--------+------+
| Skin         | 0.49    | 0.20   | 0.10   | 0.060 | 0.037  | 0    |
|              |         |        |        |       |        | .030 |
+--------------+---------+--------+--------+-------+--------+------+
| Brain        | 0.29    | 0.13   | 0.09   | 0.078 | 0.072  | 0    |
|              |         |        |        |       |        | .070 |
+--------------+---------+--------+--------+-------+--------+------+
| Other        | 0.59    | 0.25   | 0.13   | 0.083 | 0.052  | 0    |
| tissues      |         |        |        |       |        | .042 |
+--------------+---------+--------+--------+-------+--------+------+

^1^ MIRDOSE 2 software was used to calculate the radiation absorbed
dose. Assumptions on the biodistribution based on data from Gallager et
al. (*JNM* 18:10,990-996) and Jones et al. (*JNM* 23:7,613-617).

^2^ The dynamic bladder model with a uniform voiding frequency of 1.5
hours was used.

\* LLI = lower large intestine. \*\* ULI = upper large intestine

# HOW SUPPLIED

NDC \_ \_ \_ \_ \_ - \_ \_ \_ - \_ \_ [^16]

Fludeoxyglucose F 18 Injection is supplied in a
\_\_\_\_\_\_\_\_\_-dose\* septum capped \_\_\_ mL\* glass vial
containing between \_\_\_\_\_ - \_\_\_\_\_ MBq/mL\* (\_\_\_ -- \_\_\_
mCi/mL)\*^,^[^17] of no carrier added
2-deoxy-2-\[^18^F\]fluoro-D-glucose, at end of synthesis, in
approximately \_\_\_ mL.\*

This radiopharmaceutical is licensed by \[YOUR STATE \],\* Department of
Nuclear Safety, for distribution to persons licensed pursuant to \[ YOUR
STATE's Section Regulatory Code for Radioactive material specified in
Section of YOUR STATE'S Code\],\* as appropriate, or under the
equivalent licenses of an Agreement State or Licensing State.

## Storage

Fludeoxyglucose F 18 Injection should be stored upright in a lead
shielded container at controlled room temperature.

Storage and disposal of Fludeoxyglucose F 18 Injection should be in
accordance with the regulations and a general license, or its
equivalent, of an Agreement State or a Licensing State.

## Expiration Date and Time

The expiration date and time are provided on the container label.
Fludeoxyglucose F 18 Injection should be used within 8 hours from the
time of the end of synthesis.

**Caution: Rx ONLY**

Manufactured by:\*

Distributed by: \*

Your Facility Name

Complete Address

City, State and Zip Code\*

# LABELING

# IMMEDIATE CONTAINER

# VIAL/LEAD PIG

## Fludeoxyglucose F 18 Injection - \[^18^F\] FDG

## Diagnostic-For Intravenous Administration

Lot#\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Expiration
Date/Time:\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_/\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
[^18]

(12 hours after EOS)

Calibration: Date \* Time \* (EOS)

Activity Concentration: mCi\* in mL\*@ EOS

Each mL contains \_\_\_\_\_ - \_\_\_\_\_MBq\* (\_\_\_ - \_\_\_
mCi)\*^,^[^19] of no carrier added 2-deoxy-2-\[^18^F\]fluoro-D-glucose @
EOS and 9 mg of sodium chloride. Store upright in a shielded container
at controlled room temperature. Do not use if cloudy or contains
particulate matter. ^18^F Half-life = 110 min. Calculate correct dosage
from date and time of calibration. Manufactured by \_\_\_\_\_\_\_\_.\*
(radioactivity caution statement and symbol)

EOS = End of Synthesis

Caution: **Rx Only.**

**Sodium Fluoride F 18 Injection**

**Diagnostic --- For Intravenous Administration**

This guidance has been prepared by the PET Steering Committee in the
Center for Drug Evaluation and Research (CDER) at the Food and Drug
Administration. This guidance document represents the Agency\'s current
thinking on the content and format of NDAs and ANDAs for certain
positron emission tomography (PET) drug products. It does not create or
confer any rights for or on any person and does not operate to bind FDA
or the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes, regulations, or
both.

**Sodium Fluoride F 18 Injection**

**Diagnostic - For Intravenous Administration**

# DESCRIPTION

Sodium Fluoride F 18 Injection is a positron emitting
radiopharmaceutical, containing no-carrier added, radioactive fluoride F
18 that is used for diagnostic purposes in conjunction with positron
emission tomography (PET) imaging. It is administered by intravenous
injection and is produced by particle acceleration in a ^20^Ne (d, α)
^18^F nuclear reaction.

The active ingredient, sodium fluoride F 18, has the molecular formula
of Na^18^F with a molecular weight of 40.99, and has the following
chemical structure:

Na ^+^ ^18^F ^-^

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 between \_\_\_\_\_MBq to \_\_\_\_\_MBq \*
(\_\_\_\_to\_\_\_\_\_mCi)[^20] fluoride F 18, at the end of synthesis
(EOS) reference time, in 0.9% aqueous sodium chloride. The pH of the
solution is between 6 to 8. The solution does not contain any
preservatives. The only known source of nonradioactive fluorine ion
present is that found in the distilled water and saline solutions used
in preparing this product.

## Physical Characteristics

Fluorine F 18 decays by positron (+) emission and has a half-life of
110 (109.7) minutes. 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 1).

**Table 1. Principal Emission Data for Fluorine F18**

  ------------------------ ------------------ -------- ------------------------ ------- ---------- -----------------------
  **Radiation/Emission**   **% per                                                      **Mean     
                           Disintegration**                                             Energy**   

  Positron ( +)                                        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).

## External Radiation

The specific gamma ray constant for Fluorine F 18 is 6.0 R/hr/mCi (0.3
Gy/hr/kB) at 1cm. 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 2. 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 2. Radiation Attenuation of 511 keV Photons by Lead (Pb)
Shielding**

  ----------------------------------- -----------------------------------
  **Shield Thickness (Pb) mm**        **Coefficient of Attenuation**

  0                                   0.00

  4.1                                 0.50

  8.3                                 0.25

  13.2                                0.10

  26.4                                0.01

  52.8                                0.001
  ----------------------------------- -----------------------------------

For use in correcting for physical decay of this radionuclide, the
fractions remaining at selected intervals after calibration are shown in
Table 3.

**Table 3. Physical Decay Chart for Fluorine F 18\***

  -------------------------- --------------------------------------------
  **Minutes**                **Fraction Remaining**

  0                          1.00

  15                         0.909

  30                         0.826

  60                         0.683

  110                        0.500

  220                        0.250

  440                        0.060
  -------------------------- --------------------------------------------

> \*Calibration Time

# CLINICAL PHARMACOLOGY

## General

Fluorine F 18 ions normally 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.

## 

## Pharmacodynamics

Increased fluorine F 18 ion deposition around joints can occur in
arthritis or following trauma; increased deposition has also been
documented in bone around fracture sites, in osteomyelities, fibrous
dysplasia, spondylitis tuberculosa, Paget's disease, hyperstosis
frontalis interna, myositis ossificans, and in rapidly growing
epiphyses. The tendency for fluorine F 18 ions to accumulate in the
vicinity of primary and metastatic malignancy in bone has proven
clinically useful in detection of such lesions (3-10).

## Pharmacokinetics

Following intravenous administration, Sodium Fluoride F 18 Injection
provides fluorine F 18 ions that rapidly equilibrate, primarily within
the extracellular fluid space. These fluorine F 18 ions are then rapidly
cleared by bone deposition and by excretion into the urine.

## Distribution

Deposition of the fluorine F 18 ions in bone appears to be primarily a
function of blood flow to the bone and the efficiency of the bone in
extracting the fluorine F 18 ions from the blood perfusing the bone (1).
Fluorine F 18 ions do not appear to be bound to serum proteins.

### 

## Elimination

In patients with normal renal function, 20% or more of the fluorine F 18
ions are cleared from the body in the urine within the first 2 hours
after intravenous administration (3). Subsequently, small amounts of
fluorine 18 ions continue to be excreted in the urine further
diminishing the radioactivity of the fluorine F 18 ions in soft tissues
of the body. (See Pharmacokinetics section)

The clearance of fluorine F 18 ions from the blood is rapid (2).
Fluorine F 18 ions are rapidly eliminated via the renal system.

## Drug-Drug Interactions

Drug-drug interactions with Sodium Fluoride F 18 Injection have not been
studied.

# INDICATIONS

Sodium Fluoride F 18 Injection is used as a bone imaging agent to define
areas of altered osteogenic activity.

# CONTRAINDICATIONS

None known.

# WARNINGS

None known.

# 

# PRECAUTIONS

## General

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. (See Drug Handling
section.) 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 by using the smallest dose of radioactivity
consistent with safety and relative value of diagnostic information.

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

## Information for Patients

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 of Sodium Fluoride F 18
Injection. This may be achieved by having patients drink at least an 8
oz. glass of water prior to drug administration. To help protect
themselves and others in their environment, patients should take the
following precautions for 12 hours after injection: whenever possible a
toilet should be used and should be flushed several times after each
use; wash hands thoroughly after each voiding or fecal elimination. If
blood, urine, or feces soil clothing, the clothing should be washed
separately.

## Carcinogenesis, Mutagenesis, Impairment of Fertility 

Studies with Sodium Fluoride F 18 Injection have not been performed to
evaluate carcinogenic potential, mutagenic potential or effects on
fertility.

## Teratogenic Effects: Pregnancy Category C

Animal reproduction studies have not been conducted with Sodium Fluoride
F 18 Injection. It is not known whether Sodium Fluoride F 18 Injection
can cause fetal harm when administered to a pregnant woman or can affect
reproduction 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.

## Nursing Mothers

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.

## Pediatric Use

The safety and effectiveness of Sodium Fluoride F 18 Injection has not
been established in pediatric patients. Like other bone imaging agents,
Sodium Fluoride F 18 Injection is known to localize in the rapidly
growing epiphyses in developing long bones. (See Clinical Pharmacology
section.)

# Adverse Reactions 

Fluorine ions are a normal body constituent. The amount of fluorine ions
in Sodium Fluoride F 18 Injection at the indicated dose has 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. In a 1999 review of the published literature,
publicly available reference sources and adverse drug reaction reporting
systems indicated that adverse reactions have not been reported for
Sodium Fluoride F 18 Injection. However, patients should be
appropriately monitored for adverse drug reactions, and such reactions
should be reported to FDA, if they occur.

# 

# OVERDOSAGE

Overdoses of Sodium Fluoride F 18 Injection have not been reported. (See
also Radiation Dosimetry section.)

# DOSAGE AND ADMINISTRATION

The recommended dose of Sodium Fluoride F 18 Injection is 16.5 to 74.0
MBq (0.5 to 2.0 mCi), as an intravenous injection.

The maximum recommended dose should not exceed 148.0 MBq (4.0 mCi)

However, it has been estimated that use of 148.0 MBq(4.0 mCi) fluorine F
18 may result in a calculated whole body radiation dose one-sixth of
that associated with approximately 100 µCi of 85Sr, an impurity. The
dose of Sodium Fluoride F 18 Injection used in a given patient should be
minimized consistent with the objectives of the study, and the nature of
the radiation detection devices employed. (See Radiation Dosimetry
section.)

The final dose for the patient should be calculated using proper decay
factors from the time of the end of synthesis (EOS), and measured by a
suitable radioactivity calibration system before administration. (See
decay factors in Table 3.)

## Patient Preparation

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
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 fluorine F 18 radioactivity in the
lumbar spine or bony pelvis.

## Imaging

Optimally, it is recommended that imaging of Sodium Fluoride F 18
Injection can begin 1 to 2 hours after administration; however, the
longer the imaging procedure is delayed, the greater will be the ratio
of the activity in bone to that in soft tissue. Voiding immediately
prior to imaging the fluorine F 18 biodistribution in the pelvis is
recommended to reduce background radioactivity.

## Drug Handling

Sodium Fluoride F 18 Injection, like other parenteral drug products,
should be inspected visually for particulate matter and discoloration
before administration, whenever solution and container permit. Sodium
Fluoride F 18 Injection preparations containing particulate matter or
discoloration should not be administered. They should be disposed of in
a safe manner in compliance with applicable regulations.

Aseptic techniques and effective shielding should be employed in
withdrawing doses for administration to patients. Waterproof gloves and
effective shielding should be worn when handling the product.

The contents of each vial are sterile and non-pyrogenic. To maintain
sterility, aseptic technique must be used during all operations involved
in the manipulation and administration of Sodium Fluoride F 18
Injection.

As with any other radioactive material, appropriate shielding should be
used to avoid unnecessary radiation exposure to the patient,
occupational workers, and other persons.

Sodium Fluoride F 18 Injection, like other radioactive drugs, must be
handled with care, and appropriate safety measure should be used to
minimize radiation exposure to clinical personnel. Care should be taken
to minimize exposure to the patient consistent with proper patient
management. 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.

## Radiation Dosimetry

Following are the estimated absorbed radiation doses (rem/mCi) to a
human adult (70 kg) from intravenous injection of Sodium Fluoride F 18
Injection. These estimates were calculated based on human data and using
the data published by the International Commission on Radiological
Protection for Sodium Fluoride F 18 Injection.[^21] Fluorine F 18 ions
decay with a physical half-life of 109.7 minutes (1.828 hrs.).
Ninety-seven percent (97%) of the decay results in emission of a
positron with a maximum energy of 0.635 MeV, and 3% of the decay results
in electron capture with subsequent emission of characteristic X-rays of
oxygen. The bone and bone marrow are considered the target and critical
organs. The absolute values for absorbed radiation in relation to age
have not been established.

**Table 4. Estimated Absorbed Radiation Doses (rem/mCi) after
Intravenous Administration of Sodium Fluoride F 18 Injection in Adult
Humans (70kg).**

Estimated Radiation Dose

ORGAN mGy/MBq rad/mCi

Adrenals 0.0062 0.023

Brain 0.0056 0.021

Breasts 0.0028 0.010

Gallbladder wall 0.0044 0.016

LLI wall \* 0.012 0.043

Small intestine 0.0066 0.025

Stomach 0.0038 0.014

ULI wall \*\* 0.0058 0.021

Heart wall 0.0039 0.015

Kidneys 0.019 0.071

Liver 0.0040 0.015

Lungs 0.0041 0.015

Muscle 0.0060 0.022

Ovaries 0.011 0.039

Pancreas 0.0048 0.018

Red marrow 0.028 0.010

Bone surfaces 0.060 0.22

Skin 0.004 0.015

Spleen 0.0042 0.015

Testes 0.0078 0.029

Thymus 0.0035 0.013

Thyroid 0.0044 0.016

Urinary bladder wall 0.25 0.91

Uterus 0.019 0.070

Effective Dose Equivalent 0.027 mSv/MBq 0.10 rem/mCi

\*LLI -- lower large intestine. \*\* ULI = upper large intestine

Estimates were calculated using phantom of Cristy & Eckerman (Report
ORNL/TM-8381/V1 & V7). Models for bone and marrow are adopted from
Eckerman (Aspects of dosimetry of radionuclides within the skeleton with
particular emphasis on the active marrow, In Fourth International
Radiopharmaceutical Dosimetry Symposium; A.T. Schlafke‑Stelson and E. E.
Watson eds. CONF‑851113, Oak Ridge Associated Universities, Oak Ridge,
TN 37831, 1986. pp 514‑534.). Additional information was obtained from
the Radiation Internal Dose Information Center, Oak Ridge Associated
Universities, Oak Ridge, TN 37831.

# HOW SUPPLIED

NDC \_ \_ \_ \_ \_ - \_ \_ \_ - \_ \_ [^22]

Sodium Fluoride F 18 Injection is supplied in\_\_\_\_\_\_mL\*
single-dose /multiple-dose, septum capped glass vial containing
between\_\_\_\_\_\_\_-\_\_\_\_\_\_MBq/mL\*
(\_\_\_\_\_-\_\_\_\_\_mCi/mL)\* of no carrier added sodium \[18F\]
fluoride, at end of synthesis (EOS) reference time, in
approximately\_\_\_\_\_\_mL volume.\*

This radiopharmaceutical is licensed by \[YOUR STATE \]\* Department of
\[Name of Nuclear Licensing or Safety\]\* for distribution to persons
licensed pursuant to \[YOUR STATE's Regulatory Section for Radioactive
material specified in YOUR STATE's LAW\],\* as appropriate, or under the
equivalent licenses of an Agreement State or Licensing State.

## Storage

Sodium Fluoride F 18 Injection should be stored upright in a lead
shielded container at controlled room temperatures.

Storage and disposal of Sodium Fluoride F 18 Injection should be in
accordance with the regulations and a general license, or its
equivalent, of an Agreement State or a Licensing State.

## Expiration Date and Time

The expiration date and time are provided on the container label. Sodium
Fluoride F18 Injection should be used within hours\* from the time of
the end of synthesis (EOS) reference time.

Caution: **Rx ONLY**

Manufactured by:\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\*

Distributed by:\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\*

Your Facility Name

Complete Address

City, State and Zip Code\*

REFERENCES

1.  D. Van Dyke, H. O. Anger, Y. Yano, and C. Bozzini, "Bone Blood Flow
    Shown with ^18^F and the Positron Camera." Am. J. Physiology 209, 64
    (1965).

2.  D.A. Weber, E.J. Greenberg, A. Dimich, P.J. Kenny, E.O. Rothschild,
    W.P.L. Meyers and J.S. Laughlin, "Kinetics of Radionuclides used for
    Bone Sutdies," J. Nuclear Med. 10, 8 (1969).

3.  C.L. Harmen, J.E. Burns, A. Sams and M. Spittle, "The Value of ^18^F
    for Scanning Bone Tumors," Clin. Radio. 20, 204 (1969).

4.  H.J. Dworkin and E.V. Filmanowicz, "Radiofluorine Photoscanning of
    Bone for Reticulum Cell Saracoma: Early Detection of Bone
    Involvement." J. Amer. Med. Assoc. 198, 985 (1966).

5.  H.G. Kampffmeyer, H. Dworkin, E.A. Carr, and F.E. Bull, "Effect of
    Drug Therapy on the Uptake of Radioactive Fluorine by Osseous
    Metastases." Clin. Pharmacol. Ther. 8, 657 (1967).

6.  R. Spencer, R. Herbert, M.W. Rish, and W.A. Little, "Bone Scanning
    with ^85^Sr and ^18^F. Physical and Radiopharmacuetical
    Considerations and Clinical Experience in 50 Cases." Brit. J.
    Radiol. 40, 641 (1967).

7.  L.R. Holsti and L.K. Patomake, "^18^F Scanning of Primary and
    Metastatic Bone Tumors." Ann. Med. Intern. Fenn. 56, 131 (1967).

8.  R.J. French and V.R. McReady, "Use of ^18^F for Bone Scanning,"
    Brit. J. Radiol.

40, 655 (1967).

9.  N.F. Moon, H.J. Dworkin and P.D. La Fleur, "The Clinical Use of
    Sodium Fluoride

^18^F in Bone Photoscanning," J. Amer. Med. Assoc. 204, 974 (1968).

10. P. Ronai, H.S. Winchell and H.O. Anger, "Skeletal Survey for
    Metastatic Tumors of

> Bone Using ^18^F and ^85^Sr with Scintillation Camera and Whole Body
> Scanner,"
>
> J. Nuclear Med. 9, 517 (1968).

# LABELING

# IMMEDIATE CONTAINER

# VIAL/LEAD PIG

## Sodium Fluoride F 18 Injection 

## Diagnostic-For Intravenous Administration

Lot#\_\_\_\_\_\_\_\_\_\_\_\_\_\_Expiration
Date/Time:\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_/\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
[^23]

(\_\_\_ hours after EOS\*)

Calibration: Date Time \* (EOS)

Activity Concentration: mCi\* in mL\*@ EOS

Each mL contains \_\_\_\_\_ - \_\_\_\_\_MBq\* (\_\_\_ - \_\_\_
mCi)\*^,^[^24] of no carrier added sodium \[^18^F\] fluoride @ EOS\* and
9 mg of sodium chloride. Store upright in a shielded container at
controlled room temperature. Do not use if cloudy or contains
particulate matter. ^18^F Half-life = 110 min. Calculate correct dosage
from date and time of calibration. Manufactured by \_\_\_\_\_\_\_\_\*.
(radioactivity caution statement and symbol)

EOS = End of Synthesis

Caution: **Rx Only.**

[^1]: ^\*^ All missing information should be filled in by the applicant.

[^2]: Current USP standards state the specific activity should be "not
    less than 37 x 10 ^4^ MBq (10 Ci) per mmol, and the pH \<791\>
    should be "between 4.5 and 8.5." The current USP standards for
    Ammonia N 13 Injection are being revised.

[^3]: ^3^ Demer, L. L, K. L. Gould, R. A. Goldstein, R. L. Kirkeeide, N.
    A. Mullani, R. W. Smalling, A. Nishikawa, and M.E. Merhige.
    Assessment of coronary artery disease severity by PET: Comparison
    with quantitative arteriography in 193 patients. *Circulation* 1989;
    79:825-35.

[^4]: The highest recommended dose of radioactivity (20 mCi) is
    associated with a mass dose of 0.05 - 0.1 μmol (0.801 - 1.602 μg) of
    ammonia N 13.

[^5]: ^\*^ All missing information should be filled in by the applicant.

[^6]: ^\*^All missing information should be filled in by the applicant.

[^7]: ^\*^

[^8]: ^\*^ All missing information should be filled in by the applicant.

[^9]: ^\*^ All missing information should be filled in by the applicant.

[^10]: Current USP standard states the pH \<791\> should be "between 4.5
    and 8.5." The FDA approved reference listed drug has a pH range
    between 5.5 and 7.5. The current USP standards for Fludeoxyglucose F
    18 13 Injection are being revised.

[^11]: See the Agency's March 2000 PET Safety and Effectiveness Federal
    Register Notice.

[^12]: See the Agency's March 2000 PET Safety and Effectiveness Federal
    Register Notice.

[^13]: NDA #20-306.

[^14]: Jones, S. C., A. Alavi, D. Christman, I. Montanez, A. P. Wolf,
    and M. Reivich. 1982. The Radiation Dosimetry of 2-F-18
    fluoro-2-deoxy-D- glucose in Man. *J. Nucl. Med*. 23, 613-617.

[^15]: ICRP Publication 53,Volume 18, No. l-4,1987, pages 75-76.

[^16]: ^\*^ All missing information should be filled in by the
    applicant.

[^17]: The FDA approved reference listed drug has a specific
    concentration (strength) between 4 - 40 mCi/mL at EOS.

[^18]: ^\*^ All missing information should be filled in by the
    applicant.

[^19]: The FDA approved reference listed drug has a specific
    concentration (strength) between 4 - 40 mCi/mL at EOS.

[^20]: ^\*^ All missing information should be filled in by the
    applicant.

[^21]: ICRP Publication 53, Volume 18, No. l-4,1987, pages 73 - 74.

[^22]: ^\*^ All missing information should be filled in by the
    applicant.

[^23]: ^\*^ All missing information should be filled in by the
    applicant.

[^24]: The FDA approved reference listed drug has a specific
    concentration (strength) of 2.0 mCi/mL at the time of calibration
    ranging from 4.2 - 0.22 mCi/mL for an eight hour period.