Piramal Imaging, SA
1. DESCRIPTION 
Florbetaben F18 is a molecular imaging agent that binds to β-amyloid plaques in the brain, and is intended for use with PET imaging. Chemically, florbetaben F18 is described as 4-[(E)-2-(4-{2-[2-(2-[18F] fluoroethoxy) ethoxy] ethoxy}phenyl)vinyl]-N-methylaniline. The structural formula is:

Molecular weight: 358.45
Florbetaben F 18 is a sterile, non-pyrogenic radioactive diagnostic agent for intravenous injection. The clear solution is supplied ready to use. Each mL contains up to 3micrograms and 50 to 5000 MBq/mL (1.4 to135 mCi/mL) florbetaben F18 EOS, 4.4mg ascorbic acid, 118 mg ethanol, 200 mg macrogol 400, 28.8 mg sodium ascorbate. The pH of the solution is between 4.5 and 7.
2. INDICATIONS AND USAGE 
Florbetaben F 18 is indicated for Positron Emission Tomography (PET) imaging of the brain to estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being eva luated for Alzheimer’s Disease (AD) and other causes of cognitive decline.
A negative florbetaben F 18 scan indicates sparse to no amyloid neuritic plaques and is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition; a negative scan result reduces the likelihood that a patient’s cognitive impairment is due to AD. A positive florbetaben F 18 scan indicates moderate to frequent amyloid neuritic plaques; neuropathological examination has shown this amount of amyloid neuritic plaque is present in patients with AD, but may also be present in patients with other types of neurologic conditions as well as older people with normal cognition. Florbetaben F 18 is an adjunct to other diagnostic eva luations.
Limitations of Use
• A positive florbetaben F 18 scan does not establish the diagnosis of AD or any other cognitive disorder.
• Safety and effectiveness of florbetaben F 18 have not been established for:
o Predicting development of dementia or other neurologic conditions;
o Monitoring responses to therapies.
3. DOSAGE AND ADMINISTRATION 
3.1 Radiation Safety - Drug Handling
Florbetaben F 18 is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure during administration [see Warnings and Precautions (5.2)]. Use waterproof gloves and effective shielding, including lead-glass syringe shields when handling and administering florbetaben F 18. Radiopharmaceuticals, including florbetaben F 18, should only be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radioactive materials, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.
3.2 Recommended Dosing and Administration Instructions
The recommended dose of florbetaben F 18 is 300 MBq (8.1 mCi), maximum 30 mcg mass dose, administered as a single slow intravenous bolus (6 sec/mL) in a total volume of up to 10 mL.
- Inspect the radiopharmaceutical dose solution prior to administration and do not use it if it contains particulate matter
- Use aseptic technique and radiation shielding to withdraw and administer florbetaben F 18 solution.
- Measure the activity of florbetaben F 18 with a dose calibrator immediately prior to injection.
- Do not dilute florbetaben F 18.
- The injection must be intravenous in order to avoid irradiation as a result of local extravasation, as well as imaging artifacts. Verify patency of the indwelling catheter by a saline test injection prior to administration of florbetaben F 18.
- An injection (6 sec/mL) into a large vein in the arm is recommended, followed by a saline flush of approximately 10 mL.
- Dispose of unused product in a safe manner in compliance with applicable regulations
3.3 Image Acquisition Guidelines
Acquire PET images over 15 to 20 minutes starting 45 to 130 minutes after florbetaben F 18 injection. Keep the patient supine with the head positioned to center the brain, including the cerebellum, in the PET scanner field of view. Reduce head movement with tape or other flexible head restraints if necessary. Reconstruction should include attenuation correction with resulting transaxial pixel sizes between 2 and 3 mm.
3.4 Image Display and Interpretation
Florbetaben F 18 images should be interpreted only by readers who successfully complete Electronic Media- or In-Person Training provided by the manufacturer [see Warnings and Precautions (5.1)]. The objective of florbetaben F 18 image interpretation is to estimate β-amyloid neuritic plaque density in brain gray matter, not to make a clinical diagnosis. Image interpretation is performed independently of a patient’s clinical features and relies upon the recognition of image features in certain brain regions.
Image Display
PET images should be displayed in the transaxial orientation using gray scale or inverse gray scale. The sagittal and coronal planes may be used for additional orientation purposes. CT or MR images may be helpful for anatomic reference purposes. However, visual assessment should be performed using the axial planes according to the recommended reading methodology.
Image Interpretation
Interpretation of the images is made by visually comparing the activity in cortical gray matter with activity in adjacent white matter. Regions displayed in the PET images which ‘anatomically’ correspond to white matter structures (e.g., the cerebellar white matter or the splenium) should be identified to help the readers orient themselves. Images should be viewed and assessed in a systematic manner, starting with the cerebellum and scrolling up through the lateral temporal and frontal lobes, the posterior cingulate cortex/precuneus, and the parietal lobes. For a gray matter cortical region to be assessed as showing ‘tracer uptake’, the majority of slices from the respective region must be affected.
For each patient, the PET image assessment is categorized as either “β-amyloid-positive” or “β-amyloid-negative”. This determination is based on the assessment of tracer uptake in the gray matter of the following four brain regions: the temporal lobes, the frontal lobes, the posterior cingulate cortex/precuneus, and the parietal lobes; according to the following ‘rules for assessment’ [see Warnings and Precautions (5.1.)]:
• β-amyloid negative - tracer uptake (i.e., signal intensity) in gray matter is lower than in white matter in all four brain regions (no β-amyloid deposition)
• β-amyloid positive - smaller area(s) of tracer uptake equal to or higher than that present in white matter extending beyond the white matter rim to the outer cortical margin involving the majority of the slices within at least one of the four brain regions (“moderate” β-amyloid deposition), or a large confluent area of tracer uptake equal to or higher than that present in white matter extending beyond the white matter rim to the outer cortical margin and involving the entire region including the majority of slices within at least one of the four brain regions (“pronounced” β-amyloid deposition). There is no known clinical or histopathologic correlation distinguishing “moderate” from “pronounced” β-amyloid deposition.
Examples of positive and negative scans for each of the four brain regions are illustrated in Figure 1.
Figure 1. Axial view of negative (top row) and positive (bottom row) Florbetaben F 18 PET scans

Cerebellum: A contrast between the white matter (arrows) and gray matter is seen in both negative and positive scans. Extracerebral tracer uptake in scalp and in the posterior sagittal sinus (arrowhead) can be seen.
Lateral temporal lobes: Spiculated or “mountainous” appearance of the white matter (arrows) is seen in the negative scan, and. radioactive signal does not reach the outer rim of the brain (dashed line) due to lower tracer uptake in the gray matter. The positive scan shows a “plumped”, smooth appearance of the outer border of the brain parenchyma (dashed line) due to tracer uptake in the gray matter.
Frontal Lobes: Spiculated appearance of the white matter in the frontal lobes (arrows) is seen in the negative scan. The positive scan shows the tracer uptake in these regions has a “plumped”, smooth appearance due to the increased gray matter signal (dashed line).
Posterior cingulate/precuneus: Adjacent and posterior to the splenium (arrow), these regions appear as a hypo-intense “hole” (circle) in the negative scan, whereas this hole is “filled-up” (circle) in the positive scan.
Parietal lobes: In the negative scan, the midline between the parietal lobes can be easily identified (long arrow); white matter has a spiculated appearance (short arrow) with low signal near the outer rim of the brain (dashed line). In the positive scan, the midline between the parietal lobes is much thinner. The cortical areas are “filled-up” and are smooth in appearance as tracer uptake extends to the outer rim of the brain.
Some scans may be difficult to interpret due to image noise, atrophy with a thinned cortex, or image blur. If a coregistered computerized tomography (CT) image is available, the CT image may be used to clarify the relationship of the florbetaben F 18 uptake and the gray matter anatomy.
3.5 Radiation Dosimetry
The estimated radiation absorbed doses for adults from intravenous injection of florbetaben F 18 are shown in Table 1.
Table 1. Estimated Radiation Absorbed Doses from Intravenous Injection of Florbetaben F 18

The effective dose resulting from a 300 MBq (8.1 mCi) administration of florbetaben F 18 in adult subjects is 5.8 mSv. The use of a CT scan to calculate attenuation correction for reconstruction of florbetaben F 18 images (as done in PET/CT imaging) will add radiation exposure. Diagnostic head CT scans using helical scanners administer an average of 2.2 ± 1.3 mSv effective dose (CRCPD Publication E-07-2, 2007). The actual radiation dose is operator and scanner dependent. Thus, the total combined radiation exposure from florbetaben F 18 administration and subsequent scan on a PET/CT scanner is estimated to be 8 mSv.
4. CONTRAINDICATIONS 
None.
5. WARNINGS AND PRECAUTIONS 
5.1 Risk for Image Misinterpretation and other Errors
Errors may occur in the florbetaben F 18 estimation of brain neuritic β-amyloid plaque density during image interpretation. Image interpretation should be performed independently of the patient’s clinical information. The use of clinical information in the interpretation of florbetaben F 18 images has not been eva luated and may lead to errors. Errors may also occur in cases with severe brain atrophy that limits the ability to distinguish gray and white matter on the florbetaben F 18 scan. Errors may also occur due to motion artifacts that result in image distortion. Florbetaben F 18 scan results are indicative of the presence of brain neuritic β-amyloid plaques only at the time of image acquisition and a negative scan result does not preclude the development of brain neuritic β-amyloid plaques in the future.
5.2 Radiation Risk
Florbetaben F 18, similar to other radiopharmaceuticals, contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure [see Dosage and Administration (3.1)].
6. ADVERSE REACTIONS 
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in clinical practice.
The overall safety profile of florbetaben F 18 is based on data from 978 administrations of florbetaben F 18 to 872 subjects and 12 subjects who received vehicle only. No serious adverse reactions related to florbetaben F 18 administration have been reported. The most frequently observed adverse drug reactions in subjects receiving florbetaben F 18 were injection site reactions consisting of erythema, irritation and pain. All adverse reactions were mild to moderate in severity and of short duration. The most commonly reported adverse reactions (occurring in at least 0.5% of subjects) during florbetaben F 18 clinical trials are shown in Table 2.
Table 2. Adverse Reactions with a Frequency ≥0.5% Reported in Clinical Trials (n = 978 Administrations in 872 Subjects)

7. DRUG INTERACTIONS 
Drug-drug interaction studies have not been performed in patients to establish the extent, if any, to which concomitant medications may alter florbetaben F 18 image results.
8. USE IN SPECIFIC POPULATIONS 
8.1 Usage in Pregnancy
Pregnancy Category C
It is not known whether florbetaben F 18 can cause fetal harm when administered to a pregnant woman or if it can affect reproduction capacity. Animal reproduction studies have not been conducted with florbetaben F 18. All radiopharmaceuticals, including florbetaben F 18, have a potential to cause fetal harm. The likelihood of fetal harm depends on the stage of fetal development and the magnitude of the radiopharmaceutical dose. Florbetaben F 18 should be given to a pregnant woman only if clearly needed. Assess pregnancy status before administering florbetaben F 18 to a female of reproductive potential.
8.3 Nursing Mothers
It is not known whether florbetaben F 18 is excreted in human milk. Because many drugs are excreted into human milk and because of the potential for radiation exposure to nursing infants from florbetaben F 18, avoid use of the drug in a breastfeeding mother or have the mother temporarily interrupt breastfeeding for 24 hours (>10 half-lives of radioactive decay for the F 18 isotope) after exposure to florbetaben F 18. If breastfeeding is interrupted, the patient should pump and discard her breast milk and use alternate nutrition sources (e.g. stored breast milk or infant formula) for 24 hours after the administration of florbetaben F 18.
8.4 Pediatric Use
Florbetaben F 18 is not indicated for use in pediatric patients.
8.5 Geriatric Use
Of the 872 subjects in clinical studies of florbetaben F 18, 603 (69%) were 65 years or over, while 304 (35%) were 75 years or over. No overall differences in safety were observed between these subjects and younger subjects.
9. OVERDOSAGE 
A pharmacological overdose of florbetaben F 18 is unlikely given the relatively low doses used for diagnostic purposes.
In the event of administration of a radiation overdose with florbetaben F 18, the absorbed organ dose to the patient should be reduced by increasing elimination of the radionuclide from the body by inducing frequent micturition.
10. MECHANISM OF ACTION 
Florbetaben F18 is a F18-labeled stilbene derivative, which binds to β-amyloid plaques in the brain. The F 18 isotope produces a positron signal that is detected by a PET scanner. 3H-florbetaben in vitro binding experiments reveal two binding sites (Kd of 16 nM and 135 nM) in frontal cortex homogenates from patients with AD. Binding of florbetaben F18 to β-amyloid plaques in post-mortem brain sections from patients with AD using autoradiography correlates with both immunohistochemical and Bielschowsky silver stains. Florbetaben F 18 does not bind to tau or α-synuclein in tissue from patients with AD. Neither florbetaben F 18 nor non-radioactive florbetaben F 19 bind to AT8 positive tau deposits in brain tissue from patients with frontotemporal dementia (FTD), using autoradiography and immunohistochemistry, respectively.
11. PHARMACODYNAMICS  
Following intravenous administration, florbetaben F 18 crosses the blood brain barrier and shows differential retention in brain regions that contain β-amyloid deposits. Differences in signal intensity between brain regions showing specific and nonspecific florbetaben F 18 uptake form the basis for the image interpretation method.
12. PHARMACOKINETICS  
Ten minutes after intravenous bolus injection of 300 MBq of florbetaben F 18 in human volunteers, approximately 6% of the injected radioactivity was distributed to the brain. Florbetaben F 18 plasma concentrations declined by approximately 75% at 20 minutes post-injection, and by approximately 90% at 50 minutes. The F 18 in circulation during the 45-130 minute imaging window was principally associated with polar metabolites of florbetaben. Florbetaben F 18 was 98.5% bound to plasma proteins and was eliminated from plasma primarily via the hepatobiliary route with a mean biological half-life of approximately 1 hour. In vitro studies show that metabolism of florbetaben is predominantly catalyzed by CYP2J2 and CYP4F2. At 12 hours post-administration, approximately 30% of the injected radioactivity had been excreted in urine. Almost all F18 radioactivity in urine was excreted as polar metabolites of florbetaben F18 and only trace amounts of florbetaben F18 were detected.
In in vitro studies using human liver microsomes, florbetaben did not inhibit cytochrome P450 enzymes at concentrations present in vivo.
13. HOW SUPPLIED/STORAGE AND HANDLING 
1) How Available:
a) Brand name: NEURACEQ, by Piramal Imaging.
b) Generic drugs: None.
2) How Supplied:
Neuraceq is supplied in a 30 mL glass vial containing up to 30 mL of a clear solution at a strength of 50 to 5000 MBq/mL (1.4 to 135 mCi/mL) florbetaben F18 at EOS. Each vial contains multiple doses and is enclosed in a shielded container to minimize external radiation exposure.

3) Storage and Handling:
Store Neuraceq at room temperature 25°C (77°F); excursions permitted to 2°C to 42°C (36°F to 108°F).
The product does not contain a preservative. Store Neuraceq within the original container or equivalent radiation shielding. Neuraceq must not be diluted.
This preparation is approved for use by persons under license by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State.
Rx only
03/14