Flutemetamol F-18

VIZAMYL 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 VIZAMYL 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 )

Injection: 150 MBq/mL (4.05 mCi/mL) of flutemetamol F 18 in up to 30 mL volume at reference date and time as a clear, colorless to slightly yellow solution in a multiple-dose vial. Injection: 150 MBq/mL (4.05 mCi/mL) of flutemetamol F 18 in up to 30 mL volume at reference date and time in a multiple-dose vial ( 3 )

VIZAMYL is contraindicated in patients with a history of hypersensitivity reaction to VIZAMYL or polysorbate 80 [see Warnings and Precautions (5.1) ] . Known hypersensitivity to VIZAMYL or polysorbate 80 ( 4 )

Anaphylaxis and Other Serious Hypersensitivity Reactions: Always have emergency resuscitation equipment and trained personnel available at the time of VIZAMYL administration. ( 5.1 ) Risk of Image Misinterpretation and Other Errors: Image interpretation errors have been observed. ( 5.2 ) Radiation Risk: VIZAMYL contributes to a patient's long-term cumulative radiation exposure. 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. ( 2.1 , 2.2 , 5.3 )

5.1 Anaphylaxis and Other Serious Hypersensitivity Reactions Serious hypersensitivity reactions including anaphylaxis, presenting with flushing, dyspnea, and hypotension, have been observed within minutes following VIZAMYL administration. These reactions may occur in patients with no history of exposure to VIZAMYL [see Adverse Reactions (6.1 , 6.2) ] . Obtain a history of allergy or hypersensitivity reactions. Always have resuscitation equipment and trained personnel immediately available at the time of VIZAMYL administration. If a hypersensitivity reaction is suspected, immediately discontinue the injection and initiate appropriate therapy. VIZAMYL is contraindicated in patients with a history of hypersensitivity to VIZAMYL or polysorbate 80 [see Contraindications (4) ] .

5.2 Risk of Image Misinterpretation and Other Errors Errors may occur in the estimation of amyloid beta neuritic plaque density during VIZAMYL image interpretation [see Clinical Studies (14) ] . The use of clinical information in the interpretation of VIZAMYL images has not been evaluated and may lead to an inaccurate assessment. Extensive brain atrophy and motion artifacts that distort the image may limit the ability to distinguish gray and white matter on a VIZAMYL 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 or examine the striatum for VIZAMYL signal as it is less affected by atrophy [see Dosage and Administration (2.5) ] .

5.3 Radiation Risk VIZAMYL 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) ] .

The following clinically significant adverse reaction is described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Most common adverse reactions (incidence ≥ 1%) were flushing, increased blood pressure, headache, nausea, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GE HealthCare at 1-800-654-0118 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 VIZAMYL was evaluated in 761 adult subjects who received VIZAMYL by intravenous injection in clinical trials. Most subjects (70%) received a dose of 185 MBq (5 mCi). The subjects had a mean age of 62 years (range 18 years to 93 years); 45% of the subjects were male and 91% were White. A serious hypersensitivity reaction characterized by flushing, dyspnea, and chest pressure was reported within minutes following VIZAMYL administration in one subject who recovered with treatment. Adverse reactions reported in ≥ 1% of subjects from the clinical trials are shown in Table 2. Table 2: Adverse Reactions Reported in ≥ 1% of Adult Subjects Who Received VIZAMYL in Clinical Trials Adverse Reaction VIZAMYL N=761 % Flushing 2 Increased blood pressure 2 Headache 1 Nausea 1 Dizziness 1

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of VIZAMYL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders : anaphylactic reactions

Lactation: Temporarily discontinue breastfeeding. A lactating woman should pump and discard breast milk for 24 hours after VIZAMYL administration. ( 8.2 )

8.1 Pregnancy Risk Summary There are no available data on VIZAMYL use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with flutemetamol F 18 to evaluate its effect on female reproduction and embryo-fetal development. All radiopharmaceuticals, including VIZAMYL, have the potential to cause fetal harm depending on the stage of fetal development and the magnitude of the radiation dose. If considering VIZAMYL administration to a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from the drug and the gestational timing of exposure. The 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 flutemetamol F 18 or metabolites in human milk or its effects on the breastfed infant or milk production. Exposure of VIZAMYL to a breastfed infant can be minimized by temporary discontinuation of breastfeeding (see Clinical Considerations ). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VIZAMYL and any potential adverse effects on the breastfed child from VIZAMYL or from the underlying maternal condition. Clinical Considerations To decrease radiation exposure to the breastfed infant, advise a lactating woman to interrupt breastfeeding, and pump and discard breast milk for 24 hours after administration of VIZAMYL.

8.4 Pediatric Use The safety and effectiveness of VIZAMYL have not been established in pediatric patients.

8.5 Geriatric Use Of the 761 subjects in clinical studies of VIZAMYL, 447 (59%) subjects were 65 years of age and older, while 246 (32%) subjects were 75 years of age and older. No overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger adult subjects.

Flutemetamol F 18 binds to amyloid beta plaques in the brain 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 fibrillar amyloid beta, the dissociation constant (Kd) for flutemetamol was 6.7 nM. Selectivity of 3 H-flutemetamol binding in postmortem human brain sections was demonstrated using autoradiography, silver-stained protein, and immunohistochemistry (monoclonal antibody to amyloid beta) correlation studies.