2.1 Radiation Safety - Drug Handling

Vizamyl is a radioactive drug and should be handled with safety measures to minimize radiation exposure during administration [see Warnings and Precautions (5.3)]. Use waterproof gloves and effective shielding, including lead-glass syringe shields when handling and administering Vizamyl. To minimize radiation dose to the bladder, encourage patients to hydrate before and after Vizamyl administration in order to permit frequent voiding. Encourage patients to void before and after imaging with Vizamyl and frequently thereafter for 24 hours following Vizamyl administration.

Radiopharmaceuticals, including Vizamyl, should be used by or under the control of physicians who are qualified by specific training and experienced 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.

2.2 Recommended Dosing and Administration Procedures

The recommended dose for Vizamyl is 185 megabecquerels (MBq) [5 millicuries (mCi)] in a maximum dose volume of 10 mL, administered as a single intravenous bolus within 40 seconds. The maximum mass dose is 20 micrograms. Follow the injection with an intravenous flush of 5 to 15 mL of 0.9% sterile sodium chloride injection.

• Use aseptic technique and radiation shielding to withdraw and administer Vizamyl solution.
• Calculate the necessary volume to administer based on calibration time and dose using a suitably calibrated instrument.
• Visually inspect Vizamyl for particulate matter and discoloration prior to administration. Do not administer Vizamyl if it contains particulate matter or is discolored [see Description (11)].
• Do not dilute Vizamyl.
• Dispose of unused product in a safe manner in compliance with applicable regulations [see How Supplied/Storage and Handling (16)].

2.3 Imaging Acquisition Guidelines

The recommended PET scan start time is 60 to 120 minutes after Vizamyl injection, using a PET scanner in 3-D mode with appropriate data corrections. A scan duration of 10 to 20 minutes is recommended. The time of initiation and the duration of the scan may vary depending on dose, imaging acquisition, and reconstruction parameters. Position the patient supine with the brain (including the cerebellum) within a single field of view. The patient's head should be tilted so that the anterior commissure-posterior commissure (AC-PC) plane is at right angles to the bore-axis of the PET scanner, with the head positioned in a suitable head support. Reducing head movement with tape or other flexible head restraints may be employed. Iterative or filtered back-projection reconstruction is recommended with a slice thickness of 2 to 4 mm, matrix size of 128 × 128 with pixel sizes of approximately 2 mm. Where a post-smoothing filter is applied, a full width half maximum (FWHM) of not more than 5 mm is recommended; filter FWHM should be chosen to optimize the signal-to-noise ratio while preserving the sharpness of the reconstructed image.

2.4 Image Orientation and Display

2.5 Image Interpretation

Vizamyl images should be interpreted only by readers who successfully complete the electronic or in-person training program provided by the manufacturer [see Warnings and Precautions (5.2)]. The objective of Vizamyl image interpretation is to provide an estimate of the brain β-amyloid neuritic plaque density, not to make a clinical diagnosis. Image interpretation is performed independently of a patient's clinical features and relies upon recognition of image features in certain brain regions.

Image interpretation is based upon the distribution of radioactive signal within the brain; clinical information is not a component of image assessment [see Warnings and Precautions (5.2)]. Images are designated as positive or negative either by comparing radioactivity in cortical grey matter with activity in adjacent white matter, or based on the intensity in the five regions mentioned above. Signal uptake in the cerebellum does not contribute to scan interpretation (for example, a positive scan may show retained cerebellar grey-white contrast even when the cortical grey-white contrast is lost). Images should be viewed with the minimum image intensity set to zero and the maximum set such that the signal level in the easily identifiable pons is at 90% of maximum.

Negative scans show more radioactivity in white matter than in grey matter, creating clear grey-white matter contrast.

Specifically, a negative scan would have the following characteristics:

frontal, lateral temporal, inferolateral parietal lobes: gradual gradient from bright intensity of the white matter to lower intensity at the periphery of the brain; distinct sulci with concave surfaces (white matter sulcal pattern),

and

posterior cingulate and precuneus: grey matter uptake below 50-60% of peak intensity; gap of lower intensity separates two hemispheres on coronal view,

and

striatum: approximately 50% of peak intensity or lower in the region between the higher intensities of the thalamus and frontal white matter (striatal "gap")

Positive scans show at least one cortical region with reduction or loss of the normally distinct grey-white matter contrast. These scans have one or more regions with increased cortical grey matter signal (above 50-60% peak intensity) and/or reduced (or absent) grey-white matter contrast (white matter sulcal pattern is less distinct). A positive scan may have one or more regions in which grey matter radioactivity is as intense or exceeds the intensity in adjacent white matter.

Specifically, a positive scan would have the following characteristics:

frontal, lateral temporal, or inferolateral parietal lobes: high intensity seen to the periphery of the brain, with sharp reduction of intensity at the brain margin; sulci not distinct due to fill-in by high intensity grey matter resulting in a convex surface at the edge of the brain,

or

posterior cingulate and precuneus: grey matter uptake above 50-60% of peak intensity; high grey matter intensity that closes the gap between the two hemispheres on coronal view,

or

striatum: intensity above 50-60% of peak intensity; gap between thalamus and frontal white matter not distinct

If any one of the brain regions systematically reviewed for flutemetamol F 18 uptake (see Image Orientation and Display above) is positive in either hemisphere, then the scan is considered positive. Otherwise, the scan is considered negative.

Among patients with clinically important β-amyloid neuritic plaques in the brain, the temporal lobes, parietal lobes, and striatum may not be as affected compared to other brain regions. Therefore, in some images, flutemetamol F 18 signal in these regions may not be as intense as in the frontal lobes or the posterior cingulate and precuneus regions.

Atrophy may affect the interpretability of scans, particularly in the frontal, temporal and parietal lobes [see Warnings and Precautions (5.2)]. For cases in which atrophy is apparent or suspected and there is uncertainty as to the location of the grey matter on the PET scan, examine the striatum for flutemetamol F 18 signal as it is less affected by atrophy than other regions of the brain.

If the patient's MRI or CT brain images are available the interpreter should examine the CT or MRI images to clarify the relationship between PET flutemetamol F 18 uptake and grey matter anatomy.

Other factors that may affect the ability to interpret Vizamyl images include patient factors such as brain pathology, surgical changes, post-radiation therapy changes, and implants. Some scans may be difficult to interpret due to image noise, suboptimal patient positioning, or over-smoothing of the reconstructed image.

Figure 1: Axial view of negative (left) and positive (right) Vizamyl scans. The axial slices which cut through the frontal pole and inferior aspect of the splenium are shown using a rainbow color scale. The left image shows a white matter sulcal pattern at the frontal (f) and lateral temporal (lt) regions with a color intensity that tapers to the periphery, as well as less radioactivity in the striatal region(s). The right image shows absence of the white matter sulcal pattern with intensity radiating to a sharply defined convex edge, as well as more radioactivity in the striatum. In both the frontal and lateral temporal regions, the intensity is higher in the grey matter regions of the right image compared to those of the left image.

Figure 2: Sagittal view of negative (left) and positive (right) Vizamyl scans. The sagittal slices are slightly off midline in one hemisphere and shown using a rainbow color scale. In the posterior cingulate (pc) region, which is superior and posterior to the corpus callosum (cc), the left image shows intensity below 50% of peak intensity whereas the right image shows intensity above 60% of peak intensity. The pons (p) is set to approximately 90% of the maximum intensity.

Figure 3: Coronal view of negative (left) and positive (right) Vizamyl scans. The coronal slices are located posterior to the corpus callosum. The left image shows a white matter sulcal pattern in the inferior parietal (ip) regions that is not evident in the right image. Relative to the left image, the right image shows increased intensity in the posterior cinguli (pc) and increased radial extent of high intensity to the lateral surfaces of the parietal lobes particularly evident in the inferior parietal regions.

2.6 Radiation Dosimetry

The estimated absorbed radiation doses for adult patients following intravenous injection of Vizamyl are shown in Table 1. Values were calculated from human biodistribution data using OLINDA/EXM software and assuming emptying of the urinary bladder at 3.5 hour intervals.

The adult effective dose resulting from a 185-MBq (5-mCi) Vizamyl administration is 5.92 mSv. The use of a CT scan to calculate attenuation correction for reconstruction of Vizamyl images (as done in PET/CT imaging) will add radiation exposure at the level of approximately 0.1 mSv effective dose. Diagnostic head CT scans using helical scanners administer an average of 2.2 ± 1.3 mSv effective dose. The actual radiation dose is operator and scanner dependent.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions such as flushing and dyspnea have been observed within minutes following Vizamyl administration. These reactions may occur in patients with no history of prior exposure to Vizamyl.

Before administering Vizamyl, ask patients about prior reactions to drugs, especially those containing polysorbate 80.

Have resuscitation equipment and trained personnel immediately available at the time of Vizamyl administration [see Contraindications (4)].

5.2 Risk for Image Misinterpretation and Other Errors

Errors may occur while using Vizamyl PET images to estimate brain neuritic plaque density [see Clinical Studies (14)].

Image interpretation is performed independently of the patient's clinical information. The use of clinical information in the interpretation of Vizamyl images has not been evaluated and may lead to errors. Extensive brain atrophy may limit the ability to distinguish grey and white matter on a Vizamyl scan [see Dosage and Administration (2.5)]. Motion artifacts may distort the image [see Dosage and Administration (2.3)].

Vizamyl scan results are indicative of the brain neuritic amyloid plaque content only at the time of image acquisition and a negative scan result does not preclude the development of brain amyloid in the future.

5.3 Radiation Risk

Vizamyl, 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 (2.1)].

6.1 Clinical Trials Experience

Clinical trials are conducted under widely varying conditions and adverse reaction rates observed in the clinical trials of Vizamyl cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In clinical trials, 761 adults (367 men and 394 women, 91% Caucasian) with a mean age of 62 years (range 18-93 years) received Vizamyl. Most subjects (530, 70%) received a dose of 185 MBq (5 mCi).

One subject out of 761 administered Vizamyl experienced a serious hypersensitivity reaction with flushing, dyspnea and chest pressure within minutes following Vizamyl administration and recovered with treatment.

Most adverse reactions were mild to moderate in intensity and resolved spontaneously. The most commonly reported adverse reactions (occurring in at least 1% of subjects) in Vizamyl-treated subjects are shown in Table 2.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Vizamyl is not indicated for use in pediatric patients.

8.5 Geriatric Use

Of the 761 subjects in clinical studies of Vizamyl, 447 (59%) were 65 years or over, while 246 (32%) were 75 years or over. No overall differences in safety were observed between these subjects and younger subjects.

11.1 Physical Characteristics

Fluorine-18 (F 18) is a cyclotron-produced radionuclide that decays by positron emission (β+ decay, 96.7%) and orbital electron capture (3.3%) to stable oxygen-18 with a physical half-life of 109.8 minutes. The positron can undergo annihilation with an electron to produce two gamma rays; the energy of each gamma ray is 511 keV (Table 3).

11.2 External Radiation

The point source air-kerma rate constant for F-18 is 3.74E -17 Gy m2/(Bq s); this coefficient was formerly defined as the specific gamma-ray constant of 5.7 R/hr/mCi at 1 cm. The first half-value thickness of lead (Pb) for F 18 gamma rays is approximately 6 mm. The relative reduction of radiation emitted by F-18 that results from various thicknesses of lead shielding is shown in Table 4. The use of ~8 cm of Pb will decrease the radiation transmission (i.e., exposure) by a factor of about 10,000.

12.1 Mechanism of Action

Flutemetamol F 18 binds to β-amyloid plaques in the brain and the F-18 isotope produces a positron signal that is detected by a PET scanner. In in vitro binding studies using postmortem human brain homogenates containing fibrillar β-amyloid, the dissociation constant (Kd) for flutemetamol was 6.7 nM.

Selectivity of [3H]flutemetamol binding in post-mortem human brain sections was demonstrated using autoradiography, silver-stained protein, and immunohistochemistry (monoclonal antibody to β-amyloid) correlation studies.

12.2 Pharmacodynamics

Following intravenous injection, flutemetamol F 18 diffuses across the human blood-brain barrier and produces a radioactivity signal detectable throughout the brain. Subsequently, cerebral perfusion decreases the brain flutemetamol F 18 content, with differential retention of the drug in cortical areas that contain β-amyloid aggregates compared to areas that lack the aggregates. The time-activity curves for flutemetamol F 18 in the brain of subjects with positive scans shows continual signal increases from time zero through 30 minutes post administration, with stable values thereafter up to at least 120 minutes post-injection. Differences in signal intensity between brain regions that specifically retain flutemetamol F 18 and brain regions with nonspecific retention of the drug form the basis of image interpretation methods [see Dosage and Administration (2.5)].

The test-retest distribution of flutemetamol F 18 was evaluated in 5 subjects with probable AD who underwent two administrations of flutemetamol F 18 (followed by PET scans) separated by a time period of 1 to 4 weeks. Images were reproducible when evaluated semi-quantitatively using an automated assessment of SUV in pre-specified cortical regions of brain.

12.3 Pharmacokinetics

Following intravenous injection of 185 MBq (5 mCi) of Vizamyl in humans, flutemetamol F 18 plasma concentrations declined by approximately 75% in the first 20 minutes post-injection, and by approximately 90% in the first 180 minutes. The F 18 in circulation during the 30-120 minutes imaging window in plasma was principally associated with flutemetamol metabolites. Excretion was approximately 37% renal (28-45%; n=6) and 52% hepatobiliary (40-65%; n=6).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been performed to evaluate the carcinogenicity potential of flutemetamol. Flutemetamol was positive for mutagenicity in two in vitro assays: the bacterial reverse mutation assay (Ames test) and the mouse lymphoma assay.

Flutemetamol was negative for genotoxicity after in vivo exposure in rats to flutemetamol at the highest cumulative dose level tested, as measured in bone marrow micronucleus assays (157 and 27 microgram/kg/day for 2 and 14 days respectively) and an unscheduled DNA synthesis assay in rat hepatocytes (39 microgram/kg/day).

16.1 How Supplied

Vizamyl is supplied in a 30-mL multi-dose glass vial with 1-30 mL fill volume. Each vial is enclosed in an appropriate radiation shield. The total concentration is 150 MBq/mL (4.05 mCi/mL) of flutemetamol F 18 at reference date and time.

30-mL sterile multi-dose vial with variable fill volume: NDC 17156-067-30

16.2 Storage

Store Vizamyl at 2° to 30°C (36° to 86°F). The product does not contain a preservative. Store Vizamyl within radiation shielding. Do not use Vizamyl after the expiry date and time stated on the label.

16.3 Handling

Vizamyl must not be diluted. This preparation is for use by persons licensed by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State.