TAUVID

1 INDICATIONS AND USAGE TAUVID is indicated for use with positron emission tomography (PET) imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles (NFTs) in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD). TAUVID is a radioactive diagnostic agent indicated for positron emission tomography (PET) imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles (NFTs) in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD). ( 1 ) Limitations of Use TAUVID is not indicated for use in the evaluation of patients for chronic traumatic encephalopathy (CTE). ( 1 , 5.2 ) Limitations of Use TAUVID is not indicated for use in the evaluation of patients for chronic traumatic encephalopathy (CTE) [see Warnings and Precautions ( 5.2 )] .

2 DOSAGE AND ADMINISTRATION Recommended dose is 370 MBq (10 mCi), administered as a bolus intravenous injection. ( 2.2 ) Initiate imaging approximately 80 minutes after drug administration. ( 2.3 ) See full prescribing information for additional preparation, administration, imaging, and radiation dosimetry information. ( 2 ) 2.1 Radiation Safety - Drug Handling TAUVID is a radioactive drug. Only authorized persons qualified by training and experience should receive, use, and administer TAUVID. Handle TAUVID with appropriate safety measures to minimize radiation exposure during administration [see Warnings and Precautions ( 5.3 )] . Use waterproof gloves and effective shielding, including syringe shields, when preparing and handling TAUVID. 2.2 Recommended Dosage and Administration Instructions Recommended Dose The recommended amount of radioactivity to be administered for PET imaging is 370 MBq (10 mCi), administered as an intravenous bolus injection in a total volume of 10 mL or less. Preparation and Administration Assessment of pregnancy status is recommended in females of reproductive potential before administering TAUVID. Use aseptic technique and radiation shielding during the preparation and administration of TAUVID [see Dosage and Administration ( 2.1 )] . Visually inspect the radiopharmaceutical solution prior to administration. Do not use it if it contains particulate matter or if it is discolored (TAUVID is a clear, colorless solution). TAUVID may be diluted aseptically with 0.9% Sodium Chloride Injection to a maximum dilution of 1:5 by the end-user. Diluted product should be used within 4 hours of dilution and prior to product expiry. Assay the dose in a suitable dose calibrator prior to administration. Post-Administration Instructions Follow the TAUVID injection with an intravenous flush of 0.9% Sodium Chloride injection, USP. Dispose of any unused TAUVID in compliance with applicable regulations. 2.3 Image Acquisition Starting approximately 80 minutes after the TAUVID intravenous injection, obtain a 20-minute PET image with the patient supine. Position the head to center the brain (including the cerebellum) in the PET scanner field of view. Tape or other flexible head restraints may be used to reduce head movement. 2.4 Image Display The goal of the read is to identify and locate areas of flortaucipir activity in the neocortex that are greater than the background activity (background activity is defined as up to 1.65-fold the measured cerebellar average). For optimal display, select a color scale with a rapid transition between two distinct colors and adjust the scale so that the transition occurs at the 1.65-fold threshold. Examine the posterolateral temporal (PLT), occipital, parietal, and frontal regions bilaterally. Neocortical activity in either hemisphere contributes to image interpretation. Activity in white matter or regions outside the brain does not contribute to image interpretation. To help identify the PLT, consider subdividing the temporal lobe into four quadrants as instructed below. Activity in the anterior and medial temporal lobe does not contribute to image interpretation of a positive TAUVID pattern. Image Display and Orientation Display images in the transverse, sagittal, and coronal planes. Reorient images to remove head tilt in the transverse and coronal plane. Use a sagittal slice just off the midline to align the inferior frontal and inferior occipital poles in the horizontal plane. Select and Adjust the Color Scale To create a visual threshold for positivity: Draw a region of interest around the cerebellum in the transverse plane. Select the plane to go through the cerebellum at the maximum cross-sectional area of the cerebellum. Record the mean activity or cerebellar counts (MCC). The region of interest should be drawn with the scan in gray scale and in the transverse plane as seen in the example in Figure 1 . Figure 1: Example of Cerebellar Region of Interest Select a color scale for image display that has a rapid transition between two distinct colors in the general range of 25% to 60% of maximum intensity. Set the upper contrast value (UCV) of the color scale. Use the following formula to set the visual threshold of 1.65 x MCC to match the rapid transition in the color scale: UCV = (MCC x 1.65) x (100% / % level of color transition) If additional guidance on image display is needed, refer to the TAUVID User Guide for PET Image Display available by request from the manufacturer. Figure 1 2.5 Preparation for Image Interpretation Before interpreting the image, review the brain to determine the lobar anatomy. Interpret the images by first evaluating the temporal lobes, followed by occipital, parietal, and frontal lobes bilaterally. To evaluate the temporal lobes, subdivide them into four quadrants by placing the horizontal crosshair immediately posterior to the brainstem nuclei and then scrolling inferiorly to place the vertical crosshair through the widest portion of the temporal pole, thus obtaining the anterolateral temporal (ALT), anterior mesial temporal (AMT), posterolateral temporal (PLT) and posterior mesial temporal (PMT) quadrants. See Figure 2 for an example (the left and right image panels show the same scan in two different color scales). Figure 2: Temporal Lobe Quadrants Figure 2 2.6 Image Interpretation Interpret TAUVID imaging independently of the patient's clinical features and other imaging. Interpret the PET TAUVID images based upon the pattern and density of the radioactive signal within the neocortical gray matter (not within white matter or in regions outside of the brain). Only uptake of tracer in the neocortical grey matter regions should contribute to scan interpretation. Off-target binding may be seen in the choroid plexus, striatum, and brainstem nuclei. Small foci of noncontiguous tracer uptake may lead to false positive interpretation. Interpret scans that have isolated or noncontiguous, small foci in any region with caution. Some scans may be difficult to interpret due to image noise or motion artifact. For cases where there is uncertainty as to the location of neocortical uptake, use co-registered anatomical imaging to improve localization of uptake. Positive TAUVID Scan A positive scan shows increased neocortical activity in posterolateral temporal (PLT), occipital, or parietal/precuneus region(s), with or without frontal activity. Neocortical activity in either hemisphere can contribute to identification of the positive pattern. A positive scan supports the presence of widely distributed tau neuropathology (B3 tau pathology). See Figure 3 for examples (the left and right image panels show the same scans in two different color scales) [see Warnings and Precautions ( 5.1 )] . Negative TAUVID Scan A negative scan shows no increased neocortical activity, or shows increased neocortical activity isolated to the mesial temporal, anterolateral temporal, and/or frontal regions. See Figure 4 for examples (the left and right image panels show the same scans in two different color scales) [see Warnings and Precautions ( 5.1 )] . Figure 3: Positive Scan Examples A: Off target binding in the striatum. Row 1: Example of a patient with increased uptake in PLT. Row 2: Example of a patient with increased uptake in PLT and occipital regions. Rows 3 and 4: Example of a patient with increased neocortical activity in PLT, occipital lobe (solid arrows) and precuneus (dashed arrows) (row 3: level of temporal lobes, row 4: level of parietal/precuneus). Row 5: Example of a patient with increased neocortical activity in medial prefrontal/cingulate, lateral prefrontal, PLT, parietal, occipital and precuneus regions. Figure 4: Negative Scan Examples B: Off target binding in the choroid plexus or brainstem nuclei. Row 1: Example of a patient with no increased neocortical activity (activity is similar in intensity to cerebellar reference region). Row 2: Example of a patient with increased activity isolated to MTL. Row 3: Example of a patient with increased neocortical activity isolated to frontal lobe. Row 4: Example of a patient with small isolated foci of non-contiguous and variable uptake in the PLT (solid arrows); increased activity in the ALT (dashed arrows). This pattern may also be seen in the occipital or parietal region. Figure 3 Figure 4 2.7 Radiation Dosimetry Radiation absorbed dose estimates are shown in Table 1 for organs and tissues of adults from intravenous administration of TAUVID. The effective radiation dose resulting from administration of 370 MBq (10 mCi) of TAUVID to an adult weighing 70 kg is estimated to be 8.7 mSv. Critical organs include the upper large intestinal wall, small intestine, and liver. When PET/CT is performed, exposure to radiation will increase in an amount dependent on the settings used in the CT acquisition. Table 1: Estimated Radiation Absorbed Dose After a TAUVID Injection a Assumed radiation weighting factor, wr, (formerly defined as quality factor, Q) of 1 for conversion of absorbed dose (Gray or rads) to dose equivalent (Sieverts or rem) for F 18. To obtain radiation absorbed dose in rad/mCi from above table, multiply the dose in μGy/MBq by 0.0037 (e.g., 14 μGy/MBq x 0.0037 = 0.0518 rad/mCi). Organ/Tissue Mean Absorbed Dose Per Unit Administered Activity (μGy/MBq) Adrenal glands 14 Brain 8 Breasts 7 Gallbladder wall 38 Lower large intestine wall 35 Small intestine wall 85 Stomach wall 13 Upper large intestine wall 96 Heart wall 30 Kidneys 40 Liver 57 Lungs 34 Muscle 9 Ovaries 21 Pancreas 14 Red bone marrow 10 Osteogenic cells 12 Skin 6 Spleen 10 Testes 7 Thymus gland 9 Thyroid 7 Urinary bladder wall 38 Uterus 18 Total body 12 Effective dose (μSv/MBq) a 24

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Risk of Misdiagnosis in Patients Evaluated for Alzheimer's disease : Consider additional evaluation to confirm the absence of AD pathology in patients with a negative TAUVID scan. ( 2.6 , 5.1 ) Risk of Chronic Traumatic Encephalopathy Misdiagnosis : The safety and effectiveness of TAUVID have not been established for patients being evaluated for CTE. ( 1 , 5.2 ) Radiation Risk : Ensure safe drug handling to protect patients and health care workers from unintentional radiation exposure. ( 2.1 , 5.3 ) 5.1 Risk of Misdiagnosis in Patients Evaluated for Alzheimer's disease TAUVID does not target β-amyloid, one of two required components of the neuropathological diagnosis of AD. TAUVID performance for detecting tau pathology was assessed in terminally ill patients, the majority of whom had AD dementia with B3 level NFT pathology. TAUVID performance for detecting tau pathology may be lower in patients in earlier stages of the pathological spectrum [see Clinical Studies ( 14 )] . Negative TAUVID Scan NFTs may be present at levels that qualify for the neuropathological diagnosis of AD (B2 tau pathology in the presence of at least moderate levels of cortical amyloid pathology) in patients with a negative TAUVID scan. Consider additional evaluation to confirm the absence of AD pathology in patients with a negative TAUVID scan. False Positive TAUVID Scan Small foci of noncontiguous tracer uptake may lead to a false positive TAUVID scan. Only uptake of tracer in the neocortex should contribute to the interpretation of a positive TAUVID scan [see Dosage and Administration ( 2.4 )] . 5.2 Risk of Chronic Traumatic Encephalopathy Misdiagnosis The safety and effectiveness of TAUVID have not been established for patients being evaluated for CTE. Preliminary non-clinical and clinical investigations suggest differences in tau conformation and distribution may limit flortaucipir F 18 binding. Therefore, TAUVID is not indicated for detection of CTE. 5.3 Radiation Risk Diagnostic radiopharmaceuticals, including TAUVID, expose patients to radiation [see Dosage and Administration ( 2.7 )] . Radiation exposure is associated with a dose-dependent increased risk of cancer. Ensure safe handling and preparation procedures to protect patients and health care workers from unintentional radiation exposure [see Dosage and Administration ( 2.1 , 2.2 )] .

6 ADVERSE REACTIONS Most common adverse reactions (frequency ≥ 0.5%) were headache, injection site pain, and increased blood pressure. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (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 practice. In clinical studies, 1,921 study participants were exposed to TAUVID [see Clinical Studies ( 14 )] . In these studies, 885 study participants received 240 MBq of TAUVID (about 65% of the recommended dose) and 1,036 study participants received 370 MBq of TAUVID (the recommended dose). The adverse reactions reported in ≥ 0.5% of study participants are shown in Table 2 . Table 2: Adverse Reactions with a Frequency ≥0.5% in Adults Who Received TAUVID in Clinical Trials (n = 1,921) Adverse Reaction n (%) Headache 26 (1.4%) Injection site pain 23 (1.2%) Increased blood pressure 15 (0.8%) Adverse reactions with a frequency <0.5% in adults who received TAUVID in clinical trials include: Nervous system disorders: dysgeusia

8.1 Pregnancy Risk Summary All radiopharmaceuticals, including TAUVID, have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. Advise a pregnant woman of the potential risks of fetal exposure to radiation doses with administration of TAUVID. TAUVID is not likely to be used in females of reproductive age. There are no available data on TAUVID use in pregnant women. No animal reproduction studies using flortaucipir F 18 have been conducted to evaluate its effect on female reproduction and embryo-fetal development. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.