Vizamyl

In the U.S.

• Vizamyl

Available Dosage Forms:

• Solution

Therapeutic Class: Diagnostic Agent

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

Less common

• Feeling of warmth
• redness of the face, neck, arms, and occasionally, upper chest

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Dizziness
• headache
• nausea

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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.

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)].

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.

Image Orientation and Display

Image Orientation

Orient axial and coronal images to show symmetry of brain structures, with equal heights of structures bilaterally. Orient sagittal images so that the head and neck are neither flexed nor extended; the anterior and posterior aspects of the corpus callosum should be parallel to the AC-PC line as shown in Figure 2.

Image Display

• Display images with all planes (axial, sagittal and coronal planes) linked by crosshairs.
• Select a color scale that provides a progression of low through high intensity (e.g., rainbow or Sokoloff). The selected color scale should (1) provide colors that allow the reader to discriminate intensity levels above and below the intensity level of the pons, (2) provide a color for regions with little or no amyloid binding such as the cerebellar cortex, and (3) provide a range of at least five distinct colors above 50 to 60% of the peak intensity.
• Display the reference scale. Adjust the color scale to set the pons to approximately 90% maximum intensity. The cerebellar cortex should represent approximately 20-30% of peak intensity on both negative and positive Vizamyl scans.
• Briefly display axial brain slices from bottom to top and look for signs of atrophy.
• Systematically review the following brain regions (recommended plane) for flutemetamol F18 uptake as described in Image Interpretation below:
  • Frontal lobes (axial, with optional sagittal plane view)
  • Posterior cingulate and precuneus (sagittal, with optional coronal plane view)
  • Lateral temporal lobes (axial, with optional coronal plane view)
  • Inferolateral parietal lobes (coronal, with optional axial plane view)
  • Striatum (axial, with optional sagittal plane view)

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 F18 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 F18 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 F18 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 F18 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.

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.

Table 1: Adult Estimated Radiation Absorbed Vizamyl Doses in Organs/Tissues

Organ/Tissue	Absorbed Radiation Dose Per Unit Administered Activity microGy/MBq
Adrenals	13
Brain	11
Breasts	5
Gallbladder wall	287
Heart wall	14
Kidneys	31
Liver	57
Lower large intestine wall	42
Lungs	16
Muscle	9
Osteogenic cells	11
Ovaries	25
Pancreas	15
Red marrow	13
Skin	5
Small intestine wall	102
Spleen	15
Stomach wall	12
Testes	8
Thymus	6
Thyroid	6
Upper large intestine wall	117
Urinary bladder wall	145
Uterus	25
Total body	12
Effective Dose	32 (microSv/MBq)

Vizamyl injection is available in a 10-mL or 30-mL multi-dose vial containing a clear, colorless to slightly yellow solution at a strength of 150 MBq/mL [4.05 mCi/mL] of flutemetamol F 18 at reference date and time.

Pregnancy

Pregnancy Category C: It is not known whether Vizamyl 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 Vizamyl. All radiopharmaceuticals, including Vizamyl, have the potential to cause fetal harm. The likelihood of fetal harm depends on the stage of fetal development, and the magnitude of the radiopharmaceutical dose. Vizamyl should be given to a pregnant woman only if clearly needed. Assess pregnancy status before administering Vizamyl to a female of reproductive potential.

Nursing Mothers

It is not known whether flutemetamol is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for radiation exposure to nursing infants from Vizamyl, avoid use of the drug in a breastfeeding mother or have the mother temporarily interrupt breastfeeding for 24 hours (greater than 10 half-lives of radioactive decay for the F 18 isotope) after exposure to Vizamyl. If breastfeeding is interrupted, the patient should pump and discard her breast milk and use alternate infant nutrition sources (e.g., stored breast milk or infant formula) for 24 hours after administration of the drug.

Pediatric Use

Vizamyl is not indicated for use in pediatric patients.

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.

Vizamyl was evaluated in two clinical studies (Study One and Study Two) in adult subjects with a range of cognitive function, including some terminally ill patients who had agreed to participate in a post-mortem brain donation program. Both studies were single-arm and subjects underwent Vizamyl injection and scan. The images were interpreted by five independent readers masked to all clinical information; readers in Study Two were naïve to all forms of amyloid PET imaging. PET images were reviewed first without, and subsequently with, brain CT or MRI images.

Study One evaluated pre-mortem Vizamyl PET images from terminally ill patients and compared the results to postmortem truth standard assessments of cerebral cortical neuritic plaque density in patients who died during the study. Readers evaluated images using a clinically applicable binary image interpretation method (positive/negative) that involved evaluating regional Vizamyl brain uptake to yield a final overall image assessment that was compared to the truth standard. Before image interpretation, all readers underwent in-person tutoring on image interpretation. To determine the agreement between the in vivo Vizamyl image results and the post-mortem whole brain amyloid neuritic plaque density, Vizamyl results (negative/positive) were pre-specified to correspond with specific global histopathology plaque density scores, based upon a modification of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria (Table 5), which use neuritic plaque counts as a necessary pathological feature of AD. Plaques were counted on microscope slides with modified Bielschowsky silver-stained tissue sections. The global brain neuritic plaque density score for each subject was determined by averaging across the scores (0-3) for five grey matter fields per slide and then across the six slides for each of eight regions; if any one region had a regional score of greater than 1.5, the subject's brain was classified as positive for amyloid.

Table 5: Global and Regional Neuritic Plaque Score Correlates to Vizamyl Image Results

Vizamyl Image Result	CERAD Classification (Score)	Neuritic Plaque Counts
Negative	None (0)	0
	Sparse (1)	1 to 5
Positive	Moderate (2)	6 to 19
	Frequent (3)	≥20

In Study One, one hundred eighty patients were dosed with Vizamyl and 176 were imaged. The median patient age was 82 years (range 47 to 98 years) and 57% of the patients were female. By medical history 44 patients had no cognitive impairment, 135 had dementia, no patients had mild cognitive impairment (MCI), and one patient had memory loss of unspecified nature. Sixty-nine patients died during the study; 68 had cerebral cortical amyloid status determined (43 positive and 25 negative) and were included in the primary analysis. The time interval between the Vizamyl scan and death ranged from 0 to 13 months, with a median of 2.6 months, and was less than one year for 66 patients and between 12 to 13 months for 2 patients. At autopsy, the global brain neuritic plaque density category (CERAD classification as in Table 5) was available for 67/68 subjects: frequent (n = 19); moderate (n = 22); sparse (n = 14); and none (n = 12).

In Study Two, the effectiveness of an electronic training program for Vizamyl image orientation and interpretation was evaluated using Vizamyl PET images from across subjects with different cognitive abilities who had participated in earlier studies. Inter-reader reproducibility of image interpretation was assessed using images from subjects with a truth standard (68 patients who underwent an autopsy and 36 known or suspected normal pressure hydrocephalus patients with in vivo brain biopsy) and without a truth standard (28 cognitively normal volunteers 55 years or above, 80 patients with amnestic mild cognitive impairment (aMCI), 33 patients with probable AD (pAD)), and 31 young healthy volunteers. Additionally, intra-reader reproducibility was assessed from 29 images (10%). Among the 276 subjects, the median age was 72 years (range 20 to 95), 136 were females, and 251 were Caucasian.

Vizamyl performance characteristics for Study One and Study Two patients with an autopsy-based truth standard are shown in Table 6 and Table 7. Among patients who underwent autopsy (n=68; 43 positive and 25 negative based on histopathology), the median (and range) of correct read results, false negatives, and false positives were 59 (51, 61), 5 (3, 8), 3 (2, 14), respectively, for in-person training (Study One); and were 60 (55 to 61), 3 (3 to 6), 4 (2 to 10), respectively, for electronic media training (Study Two). Image reproducibility for various subject groups in Study Two is presented in Table 8. Inter-reader reproducibility analysis showed an overall Fleiss' kappa statistic of 0.83 (95% CI 0.79 to 0.86) which met the pre-specified success criterion (95% CI lower bound > 0.60). Intra-reader reproducibility analysis showed that, between the two readings for each of the 29 duplicate patient images, one of the five readers had complete agreement for all 29 images, two readers had discordant reads for a single image, and two readers had discordant reads for two images. Intra-reader reproducibility for a subgroup of 8 images from aMCI patients showed that all five readers had complete agreement for all duplicate images.

Table 6. Vizamyl Scan Results by Reader Training Method among Patients with Autopsy (n = 68)

Test Performance		In-Person Training (Study One)	Electronic Media Training (Study Two)
Sensitivity (%)	Median	88	93
	Range among the 5 readers	81 - 93	86 - 93
Specificity (%)	Median	88	84
	Range among the 5 readers	44 - 92	60 - 92

Table 7: Vizamyl Scan Interpretations by Reader Training Method among Autopsied Patients (n = 68)

		In-Person Training (Study One)					Electronic Media Training (Study Two)
		Reader					Reader
		1	2	3	4	5	6	7	8	9	10
* 43 positive and 25 negative based on histopathology
All scans with autopsies (n = 68*)	Correct	57	60	51	59	61	58	61	61	55	60
	False Negative	8	5	3	3	5	3	3	4	3	6
	False Positive	3	2	14	5	2	7	4	3	10	2

Table 8 (Study Two): Median Number of Positive Vizamyl Scans and Reproducibility of Scan Results

Subject Group by Cognitive and Truth Standard (TS)	Positive Scans N*	Kappa (95% CI)	Percent of Scans with Inter-reader Agreement
			3 of 5 readers agreed	4 of 5 readers agreed	5 of 5 readers agreed
pAD: probable AD; aMCI: amnestic MCI; Elderly: 55 years or above
* Shown is the median number of scans interpreted as positive across the 5 readers for each subgroup of subjects listed in the first column. † 30 with TS from autopsy ‡ 21 with TS from autopsy, 0 with TS from biopsy § 17 from autopsy, 5 of 36 with TS from biopsy were not definitively classified as pAD based on clinical diagnosis
All 276 subjects	139	0.83 (0.79, 0.86)	5	14	81
All subjects with a TS, n=104 (68 autopsy; 36 biopsy)	58	0.74 (0.68, 0.80)	6	24	70
All subjects without a TS, n = 172	76	0.88 (0.83, 0.92)	5	8	87
pAD, n = 63 (30 with TS†; 33 no TS)	47	0.88 (0.80, 0.96)	3	6	90
aMCI, n = 80 (0 with TS)	45	0.89 (0.82, 0.96)	4	7	89
Elderly cognitively normal without TS, n = 28	2	0.46 (0.34, 0.57)	4	14	82
Cognitively normal with TS‡, (n=21)	10	0.64 (0.5, 0.77)	5	38	57
Other (non-AD) dementia with TS, n=53§	27	0.71 (0.63, 0.80)	8	25	68

How Supplied

Vizamyl is supplied in a 10-mL or a 30-mL multi-dose glass vial with 1-10 mL and 1-30 mL fill volume respectively. 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.

10-mL sterile multi-dose vial with variable fill volume: NDC 17156-067-10

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

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.

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.

Instruct patients to inform their healthcare provider if they:

• are pregnant or breast feeding, or
• have had prior reactions to Vizamyl or any component, including polysorbate 80, or
• have reduced renal or hepatic function

Instruct patients to increase their level of hydration before and after receiving Vizamyl (Flutemetamol F 18 Injection) and to void frequently for the first 24 hours following Vizamyl administration.

Manufactured for GE Healthcare, Medi-Physics, Inc., Arlington Heights, IL 60004 U.S.A.

Vizamyl is a trademark of General Electric Company or one of its subsidiaries.
GE and the GE Monogram are trademarks of General Electric Company.

© 2017 General Electric Company – All rights reserved.

43-1067C

Revised February 2017

The clinical consequence of overdose with Vizamyl has not been reported. It is unknown whether or not flutemetamol is dialyzable. In case of overdose of radioactivity, hydration and frequent urination should be encouraged.

Applies to flutemetamol f-18: intravenous solution

Along with its needed effects, flutemetamol f-18 (the active ingredient contained in Vizamyl) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking flutemetamol f-18:

Less common

• Feeling of warmth
• redness of the face, neck, arms, and occasionally, upper chest

Some side effects of flutemetamol f-18 may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Dizziness
• headache
• nausea