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 )] .

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

ncy ≥0.5% in adults who received tauvid in clinical trials (n = 1921) adverse reaction n (%) headache 26 (1.4%) injection site pain 23 (1.2%) increased blood pressure 15 (0.8%)

d risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. 8.2 lactation risk summary there are no data on the presence of flortaucipir f 18 in human milk, or its effects on the breastfed infant or milk production. lactation studies have not been conducted in animals. advise a lactating woman to avoid breastfeeding for 4 hours after tauvid administration in order to minimize radiation exposure to a breastfed infant. 8.4 pediatric use the safety and effectiveness of tauvid in pediatric patients have not been established. 8.5 geriatric use of 1921 study participants in completed clinical studies of tauvid, 1544 (80%) tauvid-treated subjects were ≥ 65 years old, while 839 (44%) were ≥ 75 years old. no overall differences in safety or effectiveness of tauvid were observed between subjects ≥ 65 years old and younger adult subjects.

ne, a mao-b inhibitor, in vivo in low tau, high mao-b areas of the brain such as the nucleus accumbens, putamen, and caudate. however, there is little potential for mao binding to affect tauvid scan interpretation in neocortical areas. 12.3 pharmacokinetics after intravenous administration of tauvid, flortaucipir f 18 was distributed throughout the body with less than 10% of the injected f 18 radioactivity present in the blood by 5 minutes following administration, and less than 5% present in the blood by 10 minutes after administration. the residual f 18 in circulation during the 80-minute to 100-minute imaging window was approximately 28% to 34% parent, with the remainder being metabolites. clearance occurs primarily by hepatobiliary and renal excretion.

tive days.

linical evaluation around the time of tauvid imaging. table 5: study 1 tau pathology scoring tau pathology score distribution of tau nfts in the brain b0 no nfts b1 nfts limited to transentorhinal brain region b2 b1 + nfts limited to limbic brain regions b3 b2 + nfts distributed throughout the neocortex image reader performance for distinguishing b3 (positive) from b0-b2 (negative) tau pathology is shown in table 6 . table 6: study 1 tauvid scan reader performance for b3 tau pathology a ci = confidence interval. reader true positive true negative false positive false negative sensitivity % (95% ci a ) specificity % (95% ci) 1 38 17 8 1 97 (87, 100) 68 (48, 83) 2 36 23 2 3 92 (80, 97) 92 (75, 98) 3 36 22 3 3 92 (80, 97) 88 (70, 96) 4 36 19 6 3 92 (80, 97) 76 (57, 89) 5 39 13 12 0 100 (91, 100) 52 (34, 70) the performance of the five tauvid readers for sensitivity (95% ci) ranged from 92% (80, 97) to 100% (91, 100) and for specificity (95% ci) ranged from 52% (34, 70) to 92% (75, 98). exploratory analysis evaluated how the same tauvid interpretations distinguished b2-b3 from b0-b1 tau pathology, a threshold used in integrating tau and amyloid pathology for the neuropathological diagnosis of ad. in this analysis, the performance of the five tauvid readers for sensitivity (95% ci) ranged from 68% (55, 79) to 86% (74, 93) and for specificity (95% ci) ranged from 63% (31, 86) to 100% (68, 100) [see warnings and precautions ( 5.1 )] . study 2 included the same terminally ill patients as in study 1 (plus 18 additional terminally ill patients) and 159 patients with cognitive impairment being evaluated for ad (the indicated population). inter-reader agreement for five new tauvid readers was evaluated using fleiss' kappa statistic (95% ci) and found to be 0.87 (0.83, 0.91) across all 241 patients. exploratory analysis evaluated inter-reader agreement in two subgroups. in this analysis, fleiss' kappa (95% ci) was 0.82 (0.75, 0.88) in the terminally ill patients and 0.90 (0.85, 0.95) in the indicated population.

on or the relevant regulatory authority of an agreement state.