Flortaucipir F-18

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 )] .

Injection: clear, colorless solution in a 50 mL or 100 mL multiple-dose vial containing 300 MBq/mL to 3,700 MBq/mL (8.1 mCi/mL to 100 mCi/mL) flortaucipir F 18 at the end of synthesis. Injection: 300 MBq/mL to 3,700 MBq/mL (8.1 mCi/mL to 100 mCi/mL) of flortaucipir F 18 in a multiple-dose vial. ( 3 )

None. None. ( 4 )

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 )] .

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

Lactation : Interrupt breastfeeding. Advise a lactating woman to avoid breastfeeding for 4 hours after TAUVID administration. ( 8.2 )

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.

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 1,921 study participants in completed clinical studies of TAUVID, 1,544 (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, and other reported clinical experience has not identified differences in safety or effectiveness between elderly and younger patients.

Flortaucipir F 18 binds to aggregated tau protein. In the brains of patients with AD, tau aggregates combine to form NFTs, one of two components required for the neuropathological diagnosis of AD. In vitro , flortaucipir F 18 binds to paired helical filament (PHF) tau purified from brain homogenates of donors with AD. The dissociation constant (Kd) of flortaucipir F 18 binding to PHFs is 0.57 nM. In vivo , flortaucipir F 18 is differentially retained in neocortical areas that contain aggregated tau. In vitro , tritiated flortaucipir has been reported to bind with low nanomolar affinity to monoamine oxidase-A and monoamine oxidase-B, which could contribute to off target binding.