Fludeoxyglucose

Patient Information

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 (fdg) . 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.

Description

Fludeoxyglucose F 18 Injection (fdg) is a positron emitting radiopharmaceutical containing no-carrier added radioactive 2-deoxy-2-[¹⁸F]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-[¹⁸F]fluoro-D-g1ucose (Fludeoxyglucose F 18), abbreviated [¹⁸F] FDG, has a molecular formula of C₆H₁₁¹⁸FO₅ with a molecular weight of 181.26 daltons, and has the following chemical structure:

Fludeoxyglucose F 18 Injection (fdg) is provided as a ready to use isotonic, sterile, pyrogen free, clear, colorless citrate buffered solution. Each mL contains between 0.37 to 3.7 GBq (10.0 – 100 mCi) of 2-deoxy-2-[¹⁸F]fluoro-D glucose at the end of synthesis (EOS), 4.5 mg of sodium chloride and 7.2 mg of citrate ions. The pH of the solution is between 5.0 to 7.5. 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

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

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

Fludeoxyglucose F 18 Injection,USP is indicated in PET (positron emission tomography) for:

1. Identification of regions of abnormal glucose metabolism associated with foci of epileptic seizures.
2. 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 diagnosis of cancer.
3. Assessment of 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, USP is not indicated for distinguishing epileptogenic foci from brain tumors or other brain lesions which may cause seizures.

Dosage And Administration

[18F]FDG uptake may be changed by fasting or by blood sugar changes associated with diabetic mellitus. Blood glucose levels should be stabilized in non-diabetic patients by fasting before [18F]FDG injection. Diabetic patients may need stabilization of blood glucose on the day preceding and on the day of the [18F]FDG scan.

The recommended dose of [18F]FDG for an adult (70 kg) is within the range 185-370 MBq (5-10 mCi), intravenous injection. In children doses as low as 2.6 mCi have been given. Optimal dose reductions for children have not been confirmed.

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

It is recommended that PET imaging be initiated within 40 minutes of [18F]FDG injection.

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

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

[18F]FDG should be stored upright in a lead shielded environment at controlled room temperature.

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.

How Supplied

NDC 72634-001-30

Fludeoxyglucose F18 Injection, USP is supplied in a multi-dose, septum capped 30 mL glass vial containing between 148 – 1480 MBq/mL (4 — 500 mCi/mL) of no carrier added 2-deoxy-2-[18F]fluoro-D-glucose at end of synthesis, in approximately 13 mL.

This radiopharmaceutical is licensed by the North Dakota Department of Health for distribution to persons authorized to receive the licensed material pursuant to the terms and conditions of a specific license issued by the U.S. Nuclear Regulatory Commission or an Agreement State.

Storage

[18F]FDG should be stored upright in a lead shielded container at controlled room temperature.

Storage and disposal of [18F]FDG should be in accordance with the regulations and a specific license issued by the U.S. Nuclear Regulatory Commission or an Agreement State.

Expiration Date And Time

Fludeoxyglucose F18 Injection, USP should be used within 12 hours from the end of synthesis, which is provided on the container label.

Caution: Federal Law Prohibits Dispensing Without Prescription

Manufactured by: Northland Nuclear Medicine, 1815 Michigan Ave, Bismarck, ND 58504

The [18F]FDG safety data base was evaluated for 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 old; 213 patients were between 21 and 65 years old and 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.

Drug Interactions

No Information Provided

None known

Precautions

General

[18F]FDG uptake may be changed by fasting or by blood sugar changes associated with diabetic mellitus. Blood glucose levels should be stabilized in non-diabetic patients by fasting before [18F]FDG injection. Diabetic patients may need stabilization of blood glucose on the day preceding, and on the day of the [18F]FDG scan.

Patients should be monitored for arrhythmias and other manifestations of ischemia. [18F]FDG, CIDG and their metabolites theoretically could inhibit glucose metabolism. Their ability to potentiate the arrhythmogenic effects of ischemia has not been studied.

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 [18F]FDG.

[18F]FDG should be used within 12 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.

Radiopharmaceuticals should be used only by physicians who are qualified by specific training in the safe use and handling of radionuclides.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Studies with [18F]FDG 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 [18F]FDG. It is not known whether [18F]FDG can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Therefore, [18F]FDG should not be administered to a pregnant woman unless the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when [18F]FDG is administered to a nursing woman.

Pediatric Use

See Clinical Trials Section.

Overdoses of [18F]FDG have not been-reported. See Radiation Dosimetry Section for related information.

Radiation Dosimetry

The estimated absorbed radiation doses to an average human adult (70 kg) from intravenous injection of 185 MBq (5 mCi) and 370 MBq (10 mCi) of [18F]FDG are shown is Table 4. These estimates were calculated based on human1 data and using the data published by the International Commission on Radiological Protection2 for [18F]FDG.

Table 4. Estimated Absorbed Radiation Doses after intravenous administration of 2-deoxy-2-[18F]fluoro-D-glucose, [18F]FDG to a 70 kg patient.

Contraindications

None known

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.

Pharmacodynamics

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.

Pharmokinetics

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.

Metabolism

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- mannose ([¹⁸F]FDM-6-phosphate).

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.

Excretion

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

Drug-drug interactions with Fludeoxyglucose F 18 Injection (fdg) have not been evaluated

Clinical Trials

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 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 (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 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: 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 foci.

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.

REFERENCE

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