Amyvid Injection: Package Insert / Prescribing Info

2.1 Radiation Safety - Drug Handling

Handle AMYVID with appropriate safety measures to minimize radiation exposure during administration [see Warnings and Precautions (5.2)]. Use waterproof gloves and effective radiation shielding, including syringe shields when handling and administering AMYVID.

Radiopharmaceuticals, including AMYVID, should be used by or under the control of healthcare providers who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides.

2.2 Recommended Dosage and Administration Instructions

2.3 Image Acquisition Instructions

• Position the patient supine with the head positioned to center the brain, including the cerebellum, in the PET scanner field of view. Tape or other flexible head restraints may be employed to reduce head movement.
• Acquire 10-minute PET images starting 30 minutes to 50 minutes after AMYVID administration.
• Image reconstruction should include attenuation correction with resulting transaxial pixel sizes between 2 mm and 3 mm.

2.4 Image Display and Interpretation

Visual Assessment

AMYVID images should be interpreted only by readers who successfully complete the training program provided by the manufacturer.

Perform image interpretation independently of the patient's clinical features, relying on the recognition of unique image features.

Interpret AMYVID images based upon the distribution of signal intensity within the cerebral cortex by comparing the signal intensity in the cortical gray matter and the adjacent white matter. The signal intensity in the cerebellum does not contribute to the scan interpretation. For example, a positive scan may show retained cerebellar gray-white contrast even when the cortical gray-white contrast is lost.

Some scans may be difficult to interpret due to image noise, atrophy with a thinned cortical ribbon, or image blur. For cases where there is uncertainty as to the location of cortical signal, use co-registered anatomical imaging to improve localization of signal [see Warnings and Precautions (5.1)].

Negative AMYVID Scan

Negative scans show more signal in white matter than in adjacent cortical gray matter, creating clear gray-white contrast.

A negative scan indicates sparse to no amyloid beta neuritic plaques. In patients being evaluated for AD and other causes of cognitive decline who have not been treated with amyloid beta-directed therapy, a negative scan is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition and reduces the likelihood that a patient's cognitive impairment is due to AD. A negative scan result does not preclude the accumulation of amyloid beta in the brain in the future.

Positive AMYVID Scan

Positive scans show cortical areas with reduction or loss of the normally distinct gray-white contrast. These scans will have one or more areas with increased cortical gray matter signal which results in reduced (or absent) gray-white contrast. Specifically, a positive scan will have either:

a)

Two or more brain areas (each larger than a single cortical gyrus) in which there is reduced or absent gray-white contrast. This is the most common appearance of a positive scan.
or

b)

One or more areas in which cortical gray matter signal is intense and clearly exceeds the signal in adjacent white matter.

A positive scan establishes the presence of moderate to frequent amyloid beta neuritic plaques. Neuropathological examination has shown that moderate to frequent amyloid beta neuritic plaques are 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.

Figures 1, 2, and 3 provide examples of negative and positive scans.

Figure 1: Examples of AMYVID negative scans (top two rows) and positive scans (bottom two rows). Left to right panels show sagittal, coronal, and transverse PET image slices. Final panel to right shows an enlarged picture of the brain area under the box. The top two arrows are pointing to normal preserved gray-white contrast with cortical signal intensity less than the adjacent white matter. The bottom two arrows indicate areas of decreased gray-white contrast with increased cortical signal intensity that is comparable to the intensity in the adjacent white matter.

Figure 2: Typical Negative Scan. The upper (top) and lower (bottom) transverse slices both show good gray-white matter contrast. The dotted lines illustrate the edge of the cortical gray matter (outer line) and the gray-white border (inner line) and highlight the contrast between less intense signal in the gray matter and more intense signal in the white matter. The arrows illustrate the following points: A. White matter tracts can be delineated from the frontal lobe to parietal lobe. B. White matter tracts are clearly identified throughout the occipital / temporal area. C. Scalloped appearance is seen with “fingers” of white matter in the frontal cortex. D. Low levels of signal in scalp or skull are distinguished from gray matter signal by the shape and position.

Figure 3: Typical Positive Scan: The upper (top) and lower (bottom) transverse slices show loss of gray-white matter contrast in multiple brain regions. The dotted lines illustrate the edge of the cortical gray matter. Compared to the images from the negative case in Figure 2, the gray matter signal is similar to white matter signal and the gray-white matter border is more difficult to discern. The arrows show the following points: A. White matter tracts are difficult to fully identify as they travel from frontal to parietal lobe. B. Borders of white matter tracts in occipital / temporal area are lost in places. C. Gray matter in medial parietal cortex (precuneus) has increased signal. D. Low levels of signal in scalp or skull are distinguished from gray matter signal by the shape and position.

2.5 Radiation Dosimetry

Estimated radiation absorbed doses for adults from intravenous injection of AMYVID are shown in Table 1.

The whole-body effective dose resulting from administration of 370 MBq (10 mCi) of AMYVID to an adult is estimated to be 7 mSv. When PET/CT is performed, exposure to radiation will increase by an amount dependent on the settings used in the CT acquisition.

5.1 Risk of Image Misinterpretation and Other Errors

Errors may occur in the estimation of brain amyloid beta neuritic plaque density during AMYVID image interpretation [see Clinical Studies (14)].

The use of clinical information in the interpretation of AMYVID images has not been evaluated and may lead to an inaccurate assessment. Extensive brain atrophy as well as motion artifacts that distort the image may limit the ability to distinguish gray and white matter on an AMYVID scan.

Perform image interpretation independently of the patient's clinical information. For cases where there is uncertainty as to the location of cortical signal, use co-registered anatomical imaging to improve localization of signal [see Dosage and Administration (2.4)].

5.2 Radiation Risk

AMYVID 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 drug handling to protect patients and health care providers from unintentional radiation exposure. Advise patients to hydrate before and after administration and to void frequently after administration [see Dosage and Administration (2.1, 2.2)].

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 rates observed in clinical practice.

The safety of AMYVID was evaluated in 555 adult subjects who received AMYVID by intravenous injection in clinical trials. Table 2 shows adverse reactions reported in ≥ 0.4% of subjects from the clinical trials.

Adverse reactions that occurred in <0.4% of subjects included infusion site rash, dysgeusia, pruritus, urticaria, and flushing.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of AMYVID have not been established in pediatric patients.

8.5 Geriatric Use

Of the 496 patients in clinical studies of AMYVID, 307 patients were 65 years of age and older, while 203 patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients.

11.1 Drug Characteristics

AMYVID (florbetapir F 18 injection) is a radioactive diagnostic drug for intravenous use.

Chemically, florbetapir F 18 is (E)-4-(2-(6-(2-(2-(2[18F] fluoroethoxy)ethoxy)ethoxy)pyridine-3-yl)vinyl)-N-methylbenzamine. The molecular weight is 359 and the structural formula is:

AMYVID is a sterile, non-pyrogenic clear, colorless solution. Each mL contains 0.1 mcg to 19 mcg of florbetapir and 500 MBq to 1,900 MBq (13.5 mCi to 51 mCi) of florbetapir F 18 at EOS and the following inactive ingredients: 4.5 mg sodium ascorbate and 0.1 mL dehydrated alcohol in 0.9% sodium chloride injection. The pH of the solution is between 5.5 and 8.0.

11.2 Nuclear Physical Characteristics

Fluorine-18 (F 18) decays by positron (β+) emission to oxygen-18 and has a physical half-life of 109.8 minutes. The principal photons useful for diagnostic imaging are the coincident pair of 511 keV gamma photons, resulting from the interaction of the emitted positron with an electron (Table 3).

The point source air-kerma coefficient 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.

For use in correcting for physical decay of this radionuclide, the fractions remaining at selected intervals after calibration are shown in Table 5.

12.1 Mechanism of Action

Florbetapir F 18 binds to amyloid beta plaques 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 amyloid beta plaques, the dissociation constant (Kd) for florbetapir was 3.7 ± 0.3 nM. The binding of florbetapir F 18 to amyloid beta aggregates was demonstrated in postmortem human brain sections using autoradiographic methods, thioflavin S and traditional silver staining correlation studies as well as immunohistochemistry (monoclonal antibody to amyloid beta) correlation studies. Florbetapir binding to tau protein and a battery of neuroreceptors was not detected in in vitro studies.

12.2 Pharmacodynamics

Following intravenous injection, florbetapir F 18 diffuses across the human blood-brain barrier and produces a signal intensity detectable throughout the brain. Subsequently, cerebral perfusion decreases the brain florbetapir F 18 content, with differential retention of the drug in areas that contain amyloid beta aggregates compared to areas that lack the aggregates. The time-activity curves for florbetapir F 18 in the brain of subjects with positive scans show continual signal increases from time zero through 30 minutes post-administration, with stable values thereafter up to at least 90 minutes post-injection. Differences in signal intensity between brain regions showing specific and non-specific florbetapir F 18 uptake form the basis for the image interpretation method [see Dosage and Administration (2.4)].

The test-retest distribution of florbetapir F 18 was evaluated in 21 subjects (11 with probable AD and 10 healthy subjects) who underwent two administrations of florbetapir F 18 (followed by PET scans) separated by a time period of 2 to 30 days. Images were shown to maintain signal distribution reproducibility when evaluated qualitatively (by a reader blinded to image time points) as well as quantitatively using an automated assessment of standardized uptake value ratio (SUVR) in pre-specified brain regions. A comparison of a 10-minute versus a 20-minute image acquisition time showed no difference in the mean cortical to cerebellar SUVR results obtained.

12.3 Pharmacokinetics

Following intravenous administration of 370 MBq (10 mCi) of AMYVID in healthy subjects, florbetapir F 18 was distributed throughout the body with less than 5% of the injected F 18 radioactivity present in the blood by 20 minutes following administration, and less than 2% present by 45 minutes after administration. The F 18 in circulation during the 30-minute to 90-minute imaging window was principally in the form of polar florbetapir metabolites. Whole body scanning following the intravenous injection showed accumulation of radioactivity in the liver within 4 minutes post-injection, followed by elimination of the radioactivity primarily through the biliary/gastrointestinal tract. Some radioactivity is detected in the bladder. Essentially all radioactivity collected in the urine was present as polar metabolites of florbetapir F 18.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies to assess the carcinogenicity or reproductive toxicity potential of florbetapir F 18 have not been conducted.

14.1 Evaluation of AD and Other Causes of Cognitive Decline

The effectiveness of AMYVID was evaluated in two single-arm clinical studies (i.e., Studies 1 and 2) in subjects with a range of cognitive function, including some terminally ill subjects who had agreed to participate in a postmortem brain donation program as well as healthy subjects. Subjects underwent an AMYVID injection and scan. The images were interpreted using a clinically applicable binary image interpretation method (negative or positive) by five independent readers who were blinded to all clinical information [see Dosage and Administration (2.3, 2.4)]. Image interpretations used co-registration with CT scans when PET scans were performed on dual PET-CT scanners. Before image interpretation, all readers underwent special training on image interpretation: in-person training or electronic media training.

The neuritic plaque density in both studies was determined using an algorithm in which microscopic measures of highest plaque density within a brain region were averaged to produce an estimate of global neuritic plaque density. The global neuritic plaque density was categorized in the same manner as that for a region (Table 6), where plaques were counted on slides with modified Bielschowsky silver stained tissue sections. To determine the agreement between the in vivo AMYVID image results and the postmortem amyloid beta neuritic plaque density, AMYVID results (negative or positive) were pre-specified to correspond to specific histopathology-derived plaque density scores, based upon a modification of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria, which use neuritic plaque counts as a necessary pathological feature of AD.

Study 1 evaluated performance characteristics (sensitivity and specificity) in terminally ill subjects by comparing premortem AMYVID scans to a postmortem truth standard of amyloid beta neuritic plaque density. A total of 59 subjects underwent autopsy after being dosed with AMYVID and imaged. The mean age was 79 years (range 47 to 103 years), half were females, and most were White (93%). A total of 29 subjects had an AD clinical diagnosis, 13 had another type of dementing disorder, 5 had mild cognitive impairment (MCI), and 12 had no cognitive impairment. The time interval between the AMYVID scan and death was less than one year for 46 subjects and between one and two years for 13 subjects. At autopsy, the global brain neuritic plaque density category (CERAD score as in Table 6) was: frequent (n=30); moderate (n=9); sparse (n=5); and none (n=15).

Study 2 evaluated inter-reader and intra-reader reproducibility of image interpretation using images from 59 subjects with a truth standard (same subjects as in Study 1) and 92 subjects without a truth standard (52 subjects with MCI, 20 subjects with AD, and 20 healthy subjects). Intra-reader reproducibility was assessed with images from 33 subjects (22%). Among the 151 subjects, the mean age was 75 years (range 47 to 103 years), half were females, and most were White (93%).

Among all subjects who underwent autopsy within two years (n=59; 39 positive and 20 negative based on histopathology), the sensitivity using the majority interpretation of the readers trained in-person (Study 1) was 92% (95% CI: 78%, 98%) and specificity was 100% (95% CI: 80%, 100%). The median (and range) of correct, false negative, and false positive reads were 55 (45, 56), 3 (2, 12), 1 (0, 2), respectively, for in-person training; and were 51 (46 to 54), 7 (3 to 12), 1 (1 to 2), respectively, for electronic media training. Table 7 shows the inter-reader reproducibility results among readers who underwent electronic media training (Study 2) for various groups of subjects. Inter-reader reproducibility analyses for all images showed an overall Fleiss' kappa statistic of 0.83 (95% CI: 0.78, 0.88); the lower bound of the 95% CI exceeded the pre-specified success criterion of 0.58. Intra-reader reproducibility analyses showed that between the two readings for each of the 33 duplicate scans, one of the five readers had complete agreement for all 33 scans, two readers had discrepant reads for a single scan, one reader had discrepant reads for two scans, and another reader had discrepant reads for three scans.

14.2 Selection of Patients Indicated for Amyloid Beta-Directed Therapy

Refer to the Prescribing Information of amyloid beta-directed therapy for description of clinical trials in which the efficacy of amyloid beta PET for selecting patients has been established.

Brain amyloid beta PET scans have been used to assess reduction of plaque in some clinical trials of amyloid beta-directed therapies as also described in the prescribing information of the therapeutic products.

How Supplied

AMYVID (florbetapir F 18 injection) is a clear, colorless solution supplied in a shielded multiple-dose vial available as:

Storage and Handling

Store AMYVID in the original container with radiation shielding at 25ºC (77°F); excursions permitted to 15ºC to 30ºC (59°F to 86°F) [see USP Controlled Room Temperature].

AMYVID does not contain a preservative.

Do not use after the expiration date and time provided on the container label.

AMYVID multiple-dose vial expires 10 hours after EOS.

Dispose of unused product in accordance with all federal, state, and local laws and institutional requirements.

This preparation is for use by persons under license by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State.

Radiation Risk

Advise patients of the radiation risk of AMYVID. Instruct patients to drink water to ensure adequate hydration prior to administration of AMYVID and to continue drinking and voiding frequently following administration to reduce radiation exposure [see Warnings and Precautions (5.2)].

Pregnancy

Inform pregnant women of the potential risks of fetal exposure to radiation doses with AMYVID [see Use in Specific Populations (8.1)].

Lactation

Advise a lactating woman to temporarily discontinue breastfeeding and to pump and discard breast milk for 24 hours (>10 half-lives of radioactive decay for the F 18 isotope) after AMYVID administration to minimize radiation exposure to the breastfed infant [see Use in Specific Populations (8.2)].

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