Mechanism of Action
Fludeoxyglucose F 18 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 [18F] FDG-6- phosphate by the enzyme hexokinase.
Once phosphorylated it cannot 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.
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.
Fludeoxyglucose F 18 Injection (fdg) is rapidly distributed to all organs of the body after intravenous administration. After background clearance of Fludeoxyglucose F 18 Injection (fdg) , optimal PET imaging is generally achieved between 30 to 40 minutes after administration.
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.
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 ± 1.1 min, and 80-95 minutes with a mean and STD of 88 ± 4 min.
Plasma Protein Binding
The extent of binding of Fludeoxyglucose F 18 to plasma proteins is not known.
Fludeoxyglucose F 18 is transported into cells and phosphorylated to [18F]-FDG-6-
phosphate at a rate proportional to the rate of glucose utilization within that
tissue. [18F]-FDG-6-phosphate presumably is metabolized to 2-deoxy-2-[18F]fluoro-6-phospho-D-
Fludeoxyglucose F 18 Injection (fdg) 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 then excreted in the urine.
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. 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 two hours post-administration suggests that 20.6% (mean) of the radioactive dose was present 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 (fdg) 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 (fdg) study.
Drug-drug interactions with Fludeoxyglucose F 18 Injection (fdg) have not been evaluated
Oncology:1 The efficacy of Fludeoxyglucose F 18 Injection (fdg)
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 (fdg) . 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
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 (fdg) 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 (fdg) , 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 (fdg) do not preclude the diagnosis of cancer
and further work-up is indicated. Also, positive PET imaging results with Fludeoxyglucose
F 18 Injection cannot 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.
Cardiology: 2 The efficacy of Fludeoxyglucose F 18 Injection (fdg)
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 (fdg) and perfusion imaging with other diagnostic radiopharmaceuticals.
Doses of Fludeoxyglucose F 18 Injection (fdg) 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
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: 3 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 (fdg) 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 (fdg) provided new findings.
In 32% (27/87), imaging with Fludeoxyglucose F 18 Injection (fdg) 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 (fdg)
results to subsphenoidal EEG, MRI and/or surgical findings supported the concept
that the degree of hypometabolism corresponds to areas of confirmed epileptogenic
The safety and effectiveness of Fludeoxyglucose F 18 Injection (fdg) to distinguish
idiopathic epileptogenic foci from tumors or other brain lesions that may cause
seizures have not been established.
1 See March 10, 2000 Federal Register, Docket No.
00N-0553, pp. 12999-13010
2 See March 10, 2000 Federal Register, Docket No. 00N-0553, pp. 12999-13010
3 See NDA #20-306