AMYVID

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[ 18 F] 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. Structural Formula 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 ). Table 3: Principal Radiation Produced from Decay of Fluorine-18 Radiation Energy Level (keV) Abundance (%) Positron 249.8 96.9 Gamma 511 193.5 The point source air-kerma coefficient for F 18 is 3.74E -17 Gy m 2 /(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. Table 4: Radiation Attenuation of 511 keV Gamma Rays by Lead Shielding Shield Thickness cm of Lead (Pb) Coefficient of Attenuation 0.6 0.5 2 0.1 4 0.01 6 0.001 8 0.0001 For use in correcting for physical decay of this radionuclide, the fractions remaining at selected intervals after calibration are shown in Table 5 . Table 5: Physical Decay Chart for Fluorine-18 Minutes Fraction Remaining 0 1.00 15 0.909 30 0.826 60 0.683 110 0.500 220 0.250 440 0.060

AMYVID is indicated for positron emission tomography (PET) of the brain to estimate amyloid beta neuritic plaque density in adults with cognitive impairment for: Evaluation of Alzheimer's disease (AD) and other causes of cognitive decline Selection of patients who are indicated for amyloid beta-directed therapy as described in the prescribing information of the therapeutic products AMYVID is a radioactive diagnostic drug indicated for positron emission tomography (PET) of the brain to estimate amyloid beta neuritic plaque density in adults with cognitive impairment for: Evaluation of Alzheimer's disease (AD) and other causes of cognitive decline Selection of patients who are indicated for amyloid beta-directed therapy as described in the prescribing information of the therapeutic products ( 1 )

The recommended amount of radioactivity is 370 MBq (10 mCi) administered as a single intravenous bolus in a total volume of up to 10 mL. ( 2.2 ) Follow the injection with an intravenous flush of approximately 10 mL of 0.9% sodium chloride injection. ( 2.2 ) Obtain 10-minute PET images starting approximately 30 minutes to 50 minutes after drug administration. ( 2.3 ) See full prescribing information for image interpretation and radiation dosimetry. ( 2.4 , 2.5 ) 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 Recommended Dosage The recommended amount of radioactivity of AMYVID is 370 MBq (10 mCi) in a total volume of up to 10 mL, administered as a single intravenous bolus. The maximum mass dose is 50 mcg. Follow the injection with an intravenous flush of approximately 10 mL of 0.9% sodium chloride injection. Patient Preparation Instruct patients to hydrate before and after AMYVID administration and to void following AMYVID administration before imaging and frequently thereafter [see Warnings and Precautions ( 5.2 )] . Administration Use aseptic technique and radiation shielding when withdrawing and administering AMYVID. Visually inspect AMYVID for particulate matter and discoloration prior to administration. Do not use AMYVID if it contains particulate matter or if it is discolored. Do not dilute AMYVID. Assay the dose in a dose calibrator prior to administration. Inject AMYVID through a short intravenous catheter (approximately 1.5 inches or less) to minimize the potential for adsorption of the drug to the catheter. Portions of the AMYVID dose may adhere to longer catheters. Dispose of unused product in a safe manner in compliance with applicable regulations. 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 Image Display Display images in the transaxial orientation with access as needed to the sagittal and coronal planes. In reviewing the images, include all transaxial slices of the brain using a black-white scale set to the maximum intensity of all the brain pixels. Initially locate the brain slice with the highest levels of image contrast (highest signal intensity) and adjust the contrast appropriately. Start image interpretation by displaying slices sequentially from the bottom of the brain to the top. Periodically refer to the sagittal and coronal plane image display as needed to better define the signal intensity and to ensure that the entire brain is displayed. 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. Figure 1 Figure 2 Figure 3 Quantitative Analysis Quantification of amyloid beta neuritic plaque levels (e.g., Centiloid scale or standardized uptake value ratio (SUVR)) can be used in conjunction with visual assessment and performed with FDA-authorized software indicated for quantification of brain amyloid beta PET scans. Refer to the drug manufacturer's training materials for qualitative and quantitative assessment and software manufacturers' documentation for software operation. 2.5 Radiation Dosimetry Estimated radiation absorbed doses for adults from intravenous injection of AMYVID are shown in Table 1 . Table 1: Estimated Radiation Absorbed Doses in Organs/Tissues in Adults Who Received AMYVID ORGAN/TISSUE MEAN ABSORBED DOSE PER UNIT ADMINISTERED ACTIVITY (microGy/MBq) Adrenal 14 Brain 10 Breasts 6 Gallbladder Wall 143 Heart Wall 13 Kidneys 14 Liver 64 Lower Large Intestine Wall 28 Lungs 9 Muscle 9 Osteogenic Cells 28 Ovaries 18 Pancreas 14 Red Marrow 14 Skin 6 Small Intestine 66 Spleen 9 Stomach Wall 12 Testes 7 Thymus 7 Thyroid 7 Upper Large Intestine Wall 74 Urinary Bladder Wall 27 Uterus 16 Total Body 12 Effective Dose (microSv/MBq) 19 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.

None. None ( 4 )

Most common adverse reactions (incidence ≥ 0.4%) were headache, musculoskeletal pain, increased blood pressure, nausea, fatigue, injection site reaction, anxiety, back pain, claustrophobia, dizziness, feeling cold, insomnia, and neck pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-545-5979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Table 2: Adverse Reactions Reported in ≥ 0.4% of Adult Subjects Who Received AMYVID in Clinical Trials a Includes the terms blood pressure increased and hypertension. b Includes the terms injection site hemorrhage, injection site irritation, and injection site pain. c Includes the terms feeling cold and chills. Adverse Reaction AMYVID N=555 % Headache 1.8 Musculoskeletal pain 0.7 Blood pressure increased a 0.7 Nausea 0.7 Fatigue 0.5 Injection site reaction b 0.5 Anxiety 0.4 Back pain 0.4 Claustrophobia 0.4 Dizziness 0.4 Feeling cold c 0.4 Insomnia 0.4 Neck pain 0.4 Adverse reactions that occurred in <0.4% of subjects included infusion site rash, dysgeusia, pruritus, urticaria, and flushing.