Amyvid (Florbetapir F 18 Injection) Reader Training

Transcription

1 Amyvid (Florbetpir F 18 Injection) Reder Trining Imging Report (Negtive Templte) EXAMINATION: Brin Amyloid PET/CT IMAGING DATE OF STUDY: 01/02/2012 PET ID: RADIOPHARMACEUTICAL: 370 MBq (10 mci) F 18 Amyvid IV, totl volume 10 ml TECHNIQUE: 30 to 50 minutes fter injection of trcer, noncontrst CT imges were obtined for ttenution correction followed by series of overlpping emission PET imges of the brin. Imges were reconstructed nd presented in trnsverse, coronl, nd sgittl plnes. FINDINGS: There is no incresed Amyvid uptke seen in the corticl cerebrl gry mtter. The brin shows norml gry-white contrst throughout. The cerebellum hs no evidence of bnorml uptke. IMPRESSION: The scn is negtive, indicting sprse to no neuritic plques. NOTE: Amyvid is indicted for Positron Emission Tomogrphy (PET) imging of the brin to estimte β-myloid neuritic plque density in dult ptients with cognitive impirment who re being evluted for Alzheimer s Disese nd other cuses of cognitive decline. A negtive Amyvid scn indictes sprse to no neuritic plques nd is inconsistent with neuropthologicl dignosis of Alzheimer s Disese t the time of imge cquisition; negtive scn result reduces the likelihood tht ptient s cognitive impirment is due to Alzheimer s Disese. A positive Amyvid scn indictes moderte to frequent myloid neuritic plques; neuropthologicl exmintion hs shown this mount of myloid neuritic plque is present in ptients with Alzheimer s Disese, but my lso be present in ptients with other types of neurologic conditions s well s older people with norml cognition. Amyvid is n djunct to other dignostic evlutions. Limittions of Use: A positive Amyvid scn does not estblish dignosis of Alzheimer s Disese or other cognitive disorder Sfety nd effectiveness of Amyvid hve not been estblished for: Predicting development of dementi or other neurologic condition Monitoring responses to therpies Plese see pge 3 for Importnt Sfety Informtion nd pge 4 for Full Prescribing Informtion. 1

2 Amyvid (Florbetpir F 18 Injection) Reder Trining Imging Report (Positive Templte) EXAMINATION: Brin Amyloid PET/CT IMAGING DATE OF STUDY: 01/02/2012 PET ID: RADIOPHARMACEUTICAL: 370 MBq (10 mci) F 18 Amyvid IV, totl volume 10 ml TECHNIQUE: 30 to 50 minutes fter injection of trcer, noncontrst CT imges were obtined for ttenution correction followed by series of overlpping emission PET imges of the brin. Imges were reconstructed nd presented in trnsverse, coronl, nd sgittl plnes. FINDINGS: There is diffusely incresed Amyvid uptke throughout the corticl cerebrl gry mtter. Most intense uptke is seen in the prefrontl, lterl temporl, nd prietl res, with these res showing cler loss of the norml gry-white contrst. The cerebellum hs no evidence of bnorml uptke. IMPRESSION: The scn is positive, indicting moderte to frequent myloid neuritic plques. NOTE: Amyvid is indicted for Positron Emission Tomogrphy (PET) imging of the brin to estimte β-myloid neuritic plque density in dult ptients with cognitive impirment who re being evluted for Alzheimer s Disese nd other cuses of cognitive decline. A negtive Amyvid scn indictes sprse to no neuritic plques nd is inconsistent with neuropthologicl dignosis of Alzheimer s Disese t the time of imge cquisition; negtive scn result reduces the likelihood tht ptient s cognitive impirment is due to Alzheimer s Disese. A positive Amyvid scn indictes moderte to frequent myloid neuritic plques; neuropthologicl exmintion hs shown this mount of myloid neuritic plque is present in ptients with Alzheimer s Disese, but my lso be present in ptients with other types of neurologic conditions s well s older people with norml cognition. Amyvid is n djunct to other dignostic evlutions. Limittions of Use: A positive Amyvid scn does not estblish dignosis of Alzheimer s Disese or other cognitive disorder Sfety nd effectiveness of Amyvid hve not been estblished for: Predicting development of dementi or other neurologic condition Monitoring responses to therpies Lilly USA, LLC All rights reserved. AM /2013 Amyvid is trdemrk of Eli Lilly nd Compny. Plese see pge 3 for Importnt Sfety Informtion nd pge 4 for Full Prescribing Informtion. 2

3 INDICATIONS AND USAGE: Amyvid (Florbetpir F 18 Injection) is indicted for Positron Emission Tomogrphy (PET) imging of the brin to estimte bet-myloid neuritic plque density in dult ptients with cognitive impirment who re being evluted for Alzheimer s Disese (AD) nd other cuses of cognitive decline. A negtive Amyvid scn indictes sprse to no neuritic plques nd is inconsistent with neuropthologicl dignosis of AD t the time of imge cquisition; negtive scn result reduces the likelihood tht ptient s cognitive impirment is due to AD. A positive Amyvid scn indictes moderte to frequent myloid neuritic plques; neuropthologicl exmintion hs shown this mount of myloid neuritic plque is present in ptients with AD, but my lso be present in ptients with other types of neurologic conditions s well s older people with norml cognition. Amyvid is n djunct to other dignostic evlutions. Limittions of Use: A positive Amyvid scn does not estblish dignosis of AD or other cognitive disorder Sfety nd effectiveness of Amyvid hve not been estblished for: Predicting development of dementi or other neurologic condition Monitoring responses to therpies Amyvid for intrvenous use is supplied in 10 ml, 30 ml, or 50 ml multidose vils contining MBq/mL Florbetpir F 18. IMPORTANT SAFETY INFORMATION: WARNINGS AND PRECAUTIONS Risk for Imge Misinterprettion nd Other Errors Errors my occur in the Amyvid estimtion of brin neuritic plque density during imge interprettion Imge interprettion should be performed independently of the ptient s clinicl informtion. The use of clinicl informtion in the interprettion of Amyvid imges hs not been evluted nd my led to errors. Other errors my be due to extensive brin trophy tht limits the bility to distinguish gry nd white mtter on the Amyvid scn s well s motion rtifcts tht distort the imge Amyvid scn results re indictive of the brin neuritic myloid plque content only t the time of imge cquisition nd negtive scn result does not preclude the development of brin myloid in the future Rdition Risk Amyvid, similr to other rdiophrmceuticls, contributes to ptient s overll long-term cumultive rdition exposure. Long-term cumultive rdition exposure is ssocited with n incresed risk of cncer. Ensure sfe hndling to protect ptients nd helth cre workers from unintentionl rdition exposure MOST COMMON ADVERSE REACTIONS The most common dverse rections reported in clinicl trils were hedche (1.8%), musculoskeletl pin (0.8%), ftigue (0.6%), nuse (0.6%) Plese see ccompnying Full Prescribing Informtion for Amyvid. AM HCP ISI 05OCT2012 3

4 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use Amyvid sfely nd effectively. See full prescribing informtion for Amyvid. Amyvid (Florbetpir F 18 Injection) for intrvenous use Initil U.S. Approvl: 2012 INDICATIONS AND USAGE Amyvid is rdioctive dignostic gent for Positron Emission Tomogrphy (PET) imging of the brin to estimte β-myloid neuritic plque density in dult ptients with cognitive impirment who re being evluted for Alzheimer s Disese (AD) nd other cuses of cognitive decline. A negtive Amyvid scn indictes sprse to no neuritic plques, nd is inconsistent with neuropthologicl dignosis of AD t the time of imge cquisition; negtive scn result reduces the likelihood tht ptient s cognitive impirment is due to AD. A positive Amyvid scn indictes moderte to frequent myloid neuritic plques; neuropthologicl exmintion hs shown this mount of myloid neuritic plque is present in ptients with AD, but my lso be present in ptients with other types of neurologic conditions s well s older people with norml cognition. Amyvid is n djunct to other dignostic evlutions (1). Limittions of Use A positive Amyvid scn does not estblish dignosis of AD or other cognitive disorder (1). Sfety nd effectiveness of Amyvid hve not been estblished for: Predicting development of dementi or other neurologic condition; Monitoring responses to therpies (1). DOSAGE AND ADMINISTRATION Use pproprite rdition sfety hndling mesures (2.1). Administer 370 MBq (10 mci) s single intrvenous bolus in totl volume of 10 ml or less (2.2). Obtin 10-minute PET imges strting pproximtely 30 to 50 minutes fter intrvenous injection (2.3). FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Rdition Sfety - Drug Hndling 2.2 Recommended Dosing nd Administrtion Instructions 2.3 Imge Acquisition Guidelines 2.4 Imge Disply nd Interprettion 2.5 Rdition Dosimetry 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk for Imge Misinterprettion nd other Errors 5.2 Rdition Risk 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers Imge interprettion: Refer to full prescribing informtion (2.4). The rdition bsorbed dose from 370 MBq (10 mci) dose of Amyvid is 7 msv in n dult (2.5). DOSAGE FORMS AND STRENGTHS 10 ml, 30 ml, or 50 ml multidose vil contining cler, colorless injectble solution t strength of MBq/mL ( mci/ml) florbetpir F 18 t End of Synthesis (EOS) (3). CONTRAINDICATIONS None (4). WARNINGS AND PRECAUTIONS Imge interprettion errors (especilly flse negtives) hve been observed (5.1). Rdition risk: Amyvid, similr to ll rdiophrmceuticls, contributes to ptient s longterm cumultive rdition exposure. Ensure sfe hndling to protect ptients nd helth cre workers from unintentionl rdition exposure (2.1, 5.2). ADVERSE REACTIONS Most commonly reported dverse rections were: hedche (2%), musculoskeletl pin (1%), ftigue (1%), nd nuse (1%) (6). To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t LillyRx ( ) or FDA t FDA-1088 or See 17 for PATIENT COUNSELING INFORMATION 8.4 Peditric Use 8.5 Geritric Use 11 DESCRIPTION 11.1 Physicl Chrcteristics 11.2 Externl Rdition 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storge nd Hndling 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing informtion re not listed Revised: 04/2012 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Amyvid is indicted for Positron Emission Tomogrphy (PET) imging of the brin to estimte β-myloid neuritic plque density in dult ptients with cognitive impirment who re being evluted for Alzheimer s Disese (AD) nd other cuses of cognitive decline. A negtive Amyvid scn indictes sprse to no neuritic plques nd is inconsistent with neuropthologicl dignosis of AD t the time of imge cquisition; negtive scn result reduces the likelihood tht ptient s cognitive impirment is due to AD. A positive Amyvid scn indictes moderte to frequent myloid neuritic plques; neuropthologicl exmintion hs shown this mount of myloid neuritic plque is present in ptients with AD, but my lso be present in ptients with other types of neurologic conditions s well s older people with norml cognition. Amyvid is n djunct to other dignostic evlutions. Limittions of Use: A positive Amyvid scn does not estblish dignosis of AD or other cognitive disorder. Sfety nd effectiveness of Amyvid hve not been estblished for: Predicting development of dementi or other neurologic condition; Monitoring responses to therpies. 2 DOSAGE AND ADMINISTRATION 2.1 Rdition Sfety - Drug Hndling Amyvid is rdioctive drug nd should be hndled with pproprite sfety mesures to minimize rdition exposure during dministrtion [see Wrnings nd Precutions (5.1)]. Use wterproof gloves nd effective shielding, including led-glss syringe shields when hndling Amyvid. Rdiophrmceuticls, including Amyvid, should only be used by or under the control of physicins who re qulified by specific trining nd experience in the sfe use nd hndling of rdioctive mterils, nd whose experience nd trining hve been pproved by the pproprite governmentl gency uthorized to license the use of rdiophrmceuticls. 2.2 Recommended Dosing nd Administrtion Instructions The recommended dose for Amyvid is 370 MBq (10 mci), mximum 50 µg mss dose, dministered s single intrvenous bolus in totl volume of 10 ml or less. Follow the injection with n intrvenous flush of 0.9% sterile sodium chloride. Inspect the rdiophrmceuticl dose solution prior to dministrtion nd do not use it if it contins prticulte mtter or is discolored. Use septic technique nd rdition shielding to withdrw Amyvid solution. Assy the dose in suitble dose clibrtor prior to dministrtion. Inject Amyvid through short intrvenous ctheter (pproximtely 1.5 inches or less) to minimize the potentil for dsorption of the drug to the ctheter. Portions of the Amyvid dose my dhere to longer ctheters. 2.3 Imge Acquisition Guidelines A 10-minute PET imge should be cquired strting 30 to 50 minutes fter Amyvid intrvenous injection. The ptient should be supine nd the hed positioned to center the brin, including the cerebellum, in the PET scnner field of view. Reducing hed movement with tpe or other flexible hed restrints my be employed. Imge reconstruction should include ttenution correction with resulting trnsxil pixel sizes between 2 nd 3 mm. 2.4 Imge Disply nd Interprettion Amyvid imges should be interpreted only by reders who successfully complete specil trining progrm [see Wrnings nd Precutions (5.1)]. Trining is provided by the mnufcturer using either n in-person tutoril or n electronic process. The objective of Amyvid imge interprettion is to provide n estimte of the brin β-myloid neuritic plque density, not to mke clinicl dignosis. Imge interprettion is performed independently of ptient s clinicl fetures nd relies upon the recognition of unique imge fetures. Imge Disply Imges should be displyed in the trnsxil orienttion with ccess s needed to the sgittl nd coronl plnes. In reviewing the imges, include ll trnsxil slices of the brin using blck-white scle with the mximum intensity of the scle set to the mximum intensity of ll the brin pixels. Initilly locte the brin slice with the highest levels of imge contrst (highest rdioctivity signls for Amyvid uptke) nd djust the contrst ppropritely. Strt imge interprettion by displying slices sequentilly from the bottom of the brin to the top. Periodiclly refer to the sgittl nd coronl plne imge disply, s needed to better define the rdioctivity uptke nd to ensure tht the entire brin is displyed. Imge Interprettion Imge interprettion is bsed upon the distribution of rdioctive signl within the brin; clinicl informtion is not component of the imge ssessment [see Wrnings nd Precutions (5.1)]. Imges Amyvid (Florbetpir F 18 Injection) for intrvenous use PV 9200 AMP Amyvid (Florbetpir F 18 Injection) for intrvenous use PV 9200 AMP

5 re designted s positive or negtive by compring the rdioctivity in corticl gry mtter with ctivity in the djcent white mtter. This determintion is mde only in the cerebrl cortex; the signl uptke in the cerebellum does not contribute to the scn interprettion (for exmple, positive scn my show retined cerebellr gry-white contrst even when the corticl gry-white contrst is lost). Negtive scns show more rdioctivity in white mtter thn in gry mtter, creting cler grywhite contrst. Positive scns show corticl res with reduction or loss of the normlly distinct gry-white contrst. These scns hve one or more res with incresed corticl gry mtter signl which results in reduced (or bsent) gry-white contrst. Specificlly, positive scn will hve either: ) Two or more brin res (ech lrger thn single corticl gyrus) in which there is reduced or bsent gry-white contrst. This is the most common ppernce of positive scn. or b) One or more res in which gry mtter rdioctivity is intense nd clerly exceeds rdioctivity in djcent white mtter. Some scns my be difficult to interpret due to imge noise, trophy with thinned corticl ribbon, or imge blur. For cses in which there is uncertinty s to the loction or edge of gry mtter on the PET scn nd co-registered computerized tomogrphy (CT) imge is vilble (s when the study is done on PET/ CT scnner) the interpreter should exmine the CT imge to clrify the reltionship of the PET rdioctivity nd the gry mtter ntomy. Figures 1, 2, nd 3 provide exmples of negtive nd positive scns. Figure 1 demonstrtes vrying degrees of norml gry-white contrst (negtive) nd exmples where gry-white contrst hs been lost (positive). Figure 2 illustrtes typicl fetures of negtive scn, while Figure 3 shows the loss of grywhite contrst in different brin regions of positive scn. Figure 1: Exmples of Amyvid negtive scns (top two rows) nd positive scns (bottom two rows). Left to right pnels show sgittl, coronl, nd trnsverse PET imge slices. Finl pnel to right shows enlrged picture of the brin re under the box. The top two rrows re pointing to norml preserved gry-white contrst with the corticl rdioctivity less thn the djcent white mtter. The bottom two rrows indicte res of decresed gry-white contrst with incresed corticl rdioctivity tht is comprble to the rdioctivity in the djcent white mtter. Figure 2: Typicl Negtive Scn. Imges re displyed from negtive scn with upper (top) nd lower (bottom) trnsverse slices both showing good gry-white mtter contrst. On the right side of ech slice, dotted lines hve been used to illustrte the edge of the corticl gry mtter (outer line) nd the gry-white border (inner line). These dotted lines highlight contrst in uptke between the less intense uptke in the gry mtter nd the more intense uptke in the white mtter. In ddition, rrows illustrte the following points: A) White mtter trcts cn be delineted from the frontl lobe to prietl lobe. B) White mtter trcts re clerly identified throughout the occipitl / temporl re. C) Sclloped ppernce is seen with fingers of white mtter in the frontl cortex. D) Low levels of trcer in sclp or skull tht should be distinguished from gry mtter uptke by its shpe nd position. Figure 3: Typicl Positive Scn: Imges from positive scn showing upper (top) nd lower (bottom) trnsverse slices with loss of gry-white mtter contrst in multiple brin regions. On the right side of ech slice the edge of the corticl gry mtter hs been illustrted with dotted line. Compred to the imges from the negtive cse in Figure 2, the gry mtter uptke is more similr to the white mtter uptke nd the gry-white mtter border is more difficult to discern. In ddition, rrows show the following points: A) White mtter trcts re difficult to fully identify s they trvel from frontl to prietl lobe. B) Borders of white mtter trcts in occipitl / temporl re re lost in plces. C) Gry mtter in medil prietl cortex (precuneus) hs incresed uptke. D) Low levels of trcer in sclp or skull tht should be distinguished from gry mtter uptke by its shpe nd position. 2.5 Rdition Dosimetry The estimted rdition bsorbed doses for dults from intrvenous injection of Amyvid re shown in Tble 1. Tble 1: Estimted Rdition Absorbed Dose, Amyvid (Florbetpir F 18 Injection) MEAN ABSORBED DOSE PER UNIT ORGAN/TISSUE ADMINISTERED ACTIVITY(µGy/MBq) Adrenl 14 Bone - Osteogenic Cells 28 Bone - Red Mrrow 14 Brin 10 Brests 6 Gllbldder Wll 143 GI - Lower Lrge Intestine Wll 28 GI - Smll Intestine 66 GI - Stomch Wll 12 GI - Upper Lrge Intestine Wll 74 Hert Wll 13 Kidneys 14 Liver 64 Lungs 9 Muscle 9 Ovries 18 Pncres 14 Skin 6 Spleen 9 Testes 7 Thymus 7 Thyroid 7 Urinry Bldder Wll 27 Uterus 16 Totl Body 12 Effective Dose (µsv/mbq) b 19 Gstrointestinl b Assumed rdition weighting fctor, w r, (formerly defined s qulity fctor, Q) of 1 for conversion of bsorbed dose (Gry or rds) to dose equivlent (Sieverts or rem) for F 18. To obtin rdition bsorbed dose in rd/mci from bove tble, multiply the dose in µgy/mbq by , (e.g., 14 µgy/mbq x = rd/mci) The effective dose resulting from 370 MBq (10 mci) dose of Amyvid is 7.0 msv in n dult, (19 x 370 = 7030 µsv = msv). The use of CT scn to clculte ttenution correction for reconstruction of Amyvid imges (s done in PET/CT imging) will dd rdition exposure. Dignostic hed CT scns using helicl scnners dminister n verge of 2.2 ± 1.3 msv effective dose (CRCPD Publiction E-07-2, 2007). The ctul rdition dose is opertor nd scnner dependent. The totl rdition exposure from Amyvid dministrtion nd subsequent scn on PET/CT scnner is estimted to be 9 msv. 3 DOSAGE FORMS AND STRENGTHS Amyvid (Florbetpir F 18 Injection) is vilble in 10 ml, 30 ml, nd 50 ml multidose vil contining cler, colorless solution t strength of MBq/mL ( mci/ml) florbetpir F 18 t End of Synthesis (EOS). 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Risk for Imge Misinterprettion nd other Errors Errors my occur in the Amyvid estimtion of brin neuritic plque density during imge interprettion [see Clinicl Studies (14)]. Amyvid (Florbetpir F 18 Injection) for intrvenous use PV 9200 AMP Amyvid (Florbetpir F 18 Injection) for intrvenous use PV 9200 AMP

6 Imge interprettion should be performed independently of the ptient s clinicl informtion. The use of clinicl informtion in the interprettion of Amyvid imges hs not been evluted nd my led to errors. Other errors my be due to extensive brin trophy tht limits the bility to distinguish gry nd white mtter on the Amyvid scn s well s motion rtifcts tht distort the imge. Amyvid scn results re indictive of the brin neuritic myloid plque content only t the time of imge cquisition nd negtive scn result does not preclude the development of brin myloid in the future. 5.2 Rdition Risk Amyvid, similr to other rdiophrmceuticls, contributes to ptient s overll long-term cumultive rdition exposure. Long-term cumultive rdition exposure is ssocited with n incresed risk of cncer. Ensure sfe hndling to protect ptients nd helth cre workers from unintentionl rdition exposure [see Dosge nd Administrtion (2.1)]. 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes observed in clinicl prctice. In clinicl studies, 496 ptients were exposed to Amyvid. Amyvid cused no serious dverse rections in the studies nd the reported dverse rections were predominntly mild to moderte in severity. The dverse rections reported in more thn one subject within the studies re shown in Tble 2. Tble 2: Adverse Rections Reported in Clinicl Trils (N=496 ptients) Adverse Rections N (Percent of ptients) Hedche 9 (1.8%) Musculoskeletl pin 4 (0.8%) Ftigue 3 (0.6%) Nuse 3 (0.6%) Anxiety 2 (0.4%) Bck pin 2 (0.4%) Blood pressure incresed 2 (0.4%) Clustrophobi 2 (0.4%) Feeling cold 2 (0.4%) Insomni 2 (0.4%) Neck pin 2 (0.4%) 7 DRUG INTERACTIONS Phrmcodynmic drug-drug interction studies hve not been performed in ptients to estblish the extent, if ny, to which concomitnt medictions my lter Amyvid imge results. Within clinicl study of ptients with rnge of cognitive impirment, some ptients with probble AD were receiving the following medictions: donepezil, glntmine, memntine. Men corticl Stndrdized Uptke Vlue (SUV) rtios did not differ between the ptients tking or not tking these concomitnt medictions. In in vitro tests, none of the drugs tested, including the cetylcholinesterse inhibitors donepezil, glntmine, nd tcrine, ltered florbetpir F 18 binding to its trget. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Pregnncy Ctegory C. It is not known whether Amyvid cn ffect reproductive cpcity or cuse fetl hrm when dministered to pregnnt womn. Animl reproduction studies hve not been conducted with Amyvid. Amyvid should be dministered to pregnnt womn only if clerly needed. All rdiophrmceuticls, including Amyvid, hve potentil to cuse fetl hrm. The likelihood of fetl hrm depends on the stge of fetl development nd the mgnitude of the rdiophrmceuticl dose. Assess pregnncy sttus before dministering Amyvid to femle of reproductive potentil. 8.3 Nursing Mothers It is not known whether Amyvid is excreted in humn milk. Becuse mny drugs re excreted into humn milk nd becuse of the potentil for rdition exposure to nursing infnts from Amyvid, void use of the drug in brestfeeding mother or hve the mother temporrily interrupt brestfeeding for 24 hours (>10 hlf-lives of rdioctive decy for the F 18 isotope) fter exposure to Amyvid. If brestfeeding is interrupted, the ptient should pump nd discrd her brest milk nd use lternte infnt nutrition sources (e.g., stored brest milk or infnt formul) for 24 hours fter dministrtion of the drug. 8.4 Peditric Use Amyvid is not indicted for use in peditric ptients. 8.5 Geritric Use Of 496 ptients in completed clinicl studies of Amyvid, 307 ptients were 65 yers old (203 ptients were over 75 yers of ge). No overll differences in sfety or effectiveness were observed between these subjects nd younger subjects. 11 DESCRIPTION Amyvid contins florbetpir F 18, moleculr imging gent tht binds to β-myloid ggregtes, nd is intended for use with PET imging of the brin. Chemiclly, florbetpir F 18 is described s (E)-4-(2- (6-(2-(2-(2[ 18 F] fluoroethoxy)ethoxy)ethoxy)pyridine-3-yl)vinyl)-n-methylbenzmine. The moleculr weight is 359 nd the structurl formul is: HN N Amyvid is sterile, non-pyrogenic rdioctive dignostic gent for intrvenous injection. The cler, colorless solution is supplied redy to use nd ech milliliter contins 0.1 to 19 microgrms of florbetpir nd MBq ( mci) florbetpir F 18 t EOS, 4.5 mg sodium scorbte USP nd 0.1 ml dehydrted lcohol USP in 0.9% sodium chloride injection USP. The ph of the solution is between 5.5 nd 7.5. O O O 18 F 11.1 Physicl Chrcteristics Amyvid is rdiolbeled with [ 18 F] fluorine (F 18) tht decys by positron (β + ) emission to O 18 nd hs hlf-life of minutes. The principl photons useful for dignostic imging re the coincident pir of 511 kev gmm photons, resulting from the interction of the emitted positron with n electron (Tble 3). Tble 3: Principl Rdition Produced from Decy of Fluorine 18 Rdition Energy Level (kev) Abundnce (%) Positron Gmm Externl Rdition The point source ir-kerm coefficient for F-18 is 3.74E -17 Gy m 2 /(Bq s); this coefficient ws formerly defined s the specific gmm-ry constnt of 5.7 R/hr/mCi t 1 cm. The first hlf-vlue thickness of led (Pb) for F 18 gmm rys is pproximtely 6 mm b. The reltive reduction of rdition emitted by F-18 tht results from vrious thicknesses of led shielding is shown in Tble 4. The use of ~8 cm of Pb will decrese the rdition trnsmission (i.e., exposure) by fctor of bout 10,000. Tble 4: Rdition Attenution of 511 kev Gmm Rys by Led Shielding Shield Thickness Coefficient of Attenution cm of led (Pb) Eckermn KF nd A Endo. MIRD: Rdionuclide Dt nd Decy Schemes, 2 nd Edition, b Derived from dt in NCRP Report No , Appendix C 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action Florbetpir F 18 binds to β-myloid plques nd the F 18 isotope produces positron signl tht is detected by PET scnner. In in vitro binding studies using postmortem humn brin homogentes contining β-myloid plques, the dissocition constnt (K d ) for florbetpir ws 3.7 ± 0.3 nm. The binding of florbetpir F 18 to β-myloid ggregtes ws demonstrted in postmortem humn brin sections using utordiogrphic methods, thioflvin S nd trditionl silver stining correltion studies s well s monoclonl ntibody β-myloid-specific correltion studies. Florbetpir binding to tu protein nd bttery of neuroreceptors ws not detected in in vitro studies Phrmcodynmics Following intrvenous injection, florbetpir F 18 diffuses cross the humn blood-brin brrier nd produces rdioctivity signl detectble throughout the brin. Subsequently, cerebrl perfusion decreses the brin florbetpir F 18 content, with differentil retention of the drug in res tht contin β-myloid ggregtes compred to res tht lck the ggregtes. The time-ctivity curves for florbetpir F 18 in the brin of subjects with positive scns show continul signl increses from time zero through 30 minutes post-dministrtion, with stble vlues therefter up to t lest 90 minutes post-injection. Differences in the signl intensity between portions of the brin tht specificlly retin florbetpir F 18 nd the portions of the brin with nonspecific retention of the drug forms the imge interprettion methods [see Dosge nd Administrtion (2.5)]. Clinicl studies evluted the test-retest distribution of florbetpir F 18 within the brins of 21 subjects (11 with probble AD nd 10 helthy volunteers) who underwent two injections (with PET scns), seprted by time period of 2 to 30 dys. Imges were shown to mintin signl distribution reproducibility when evluted qulittively (by reder msked to imge time points) s well s quntittively using n utomted ssessment of SUV in pre-specified brin regions. A comprison of 10-minute imge cquisition time versus 20-minute cquisition time showed no difference in the men corticl to cerebellr SUV rtio results obtined Phrmcokinetics Following the intrvenous dministrtion of 370 MBq (10 mci) of florbetpir F 18 to helthy volunteers, the drug ws distributed throughout the body with less thn 5% of the injected F 18 rdioctivity present in the blood by 20 minutes following dministrtion, nd less thn 2% present by 45 minutes fter dministrtion. The residul F 18 in circultion during the minute imging window ws principlly in the form of polr F 18 metbolites. Whole body scnning following the intrvenous injection showed ccumultion of rdioctivity in the liver within four minutes post-injection, followed by elimintion of the rdioctivity predominntly through the biliry/gstrointestinl trct with much lower rdioctivity detected in the bldder. Essentilly ll rdioctivity collected in the urine ws present s polr metbolites of florbetpir F NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Animl studies to ssess the crcinogenicity or reproductive toxicity potentils of Amyvid hve not been conducted. In n in vitro bcteril reverse muttion ssy (Ames test), increses in the number of revertnt colonies were observed in 2 of the 5 strins exposed to 19 F-AV-45, the non-rdioctive form of florbetpir F 18. In chromosoml berrtion in vitro study with cultured humn peripherl lymphocytes, 19 F-AV-45 did not increse the percentge of cells with structurl berrtions with 3-hour exposure with or without ctivtion; however, 22-hour exposure produced sttisticlly significnt increse in structurl berrtions t ll tested concentrtions. Potentil in vivo genotoxicity of 19 F-AV-45 ws evluted in mouse micronucleus study. In this ssy, 19 F-AV-45 did not increse the number of micronucleted polychromtic erythrocytes t the highest chievble dose level, 372 µg/kg/dy, when given twice dily for 3 consecutive dys. 14 CLINICAL STUDIES Amyvid ws evluted in three clinicl studies tht exmined imges from helthy dult subjects s well s subjects with rnge of cognitive disorders, including some terminlly ill ptients who hd greed Amyvid (Florbetpir F 18 Injection) for intrvenous use PV 9200 AMP Amyvid (Florbetpir F 18 Injection) for intrvenous use PV 9200 AMP

7 to prticipte in postmortem brin dontion progrm. All the studies were single rm studies in which subjects underwent n Amyvid injection nd scn nd then hd imges interpreted by multiple independent reders who were msked to ll clinicl informtion. Imge interprettions used co-registrtion with CT scns when PET scns were performed on dul PET-CT scnners. In Study One, semi-quntittive Amyvid imge interprettion method, which is not intended for clinicl use, ws used by three reders to interpret imges from 152 terminlly ill ptients, of whom 35 underwent utopsy (29 included in primry nlysis). The medin ptient ge ws 85 yers (rnge 55 to 103 yers) nd 14 of the ptients were femle. Eighteen of the ptients hd dementi, 9 hd no cognitive impirment nd 2 hd mild cognitive impirment (MCI). The min study outcome ws comprison of premortem Amyvid imges to the findings from postmortem brin exmintion (truth stndrd). The semi-quntittive mesures consisted of five-point whole brin Amyvid uptke imge scoring outcome tht ws compred to globl score of the percentge of the whole brin tht contined myloid, s determined by immunohistochemicl microscopy. The percentge of postmortem corticl myloid burden rnged from 0 to 9% nd correlted with the medin Amyvid scores (Spermn s rho=0.78; p<0.0001, 95% CI, 0.58 to 0.89). Studies Two nd Three used cliniclly-pplicble binry imge interprettion method (positive/ negtive) to evlute imges from rnge of ptients who hd prticipted in erlier studies. The studies ssessed performnce chrcteristics (sensitivity nd specificity) mong subjects with postmortem myloid neuritic plque density truth stndrd. Additionlly, inter-reder nd intr-reder imge interprettion reproducibility ws ssessed mong ll the subjects, including subjects who lcked postmortem truth stndrd. Before imge interprettion, ll reders underwent specil trining: Study Two used n in-person tutoring type of trining nd Study Three used n electronic medi-bsed trining method. Five trined reders interpreted imges independently within ech study. The brin neuritic plque density in both studies ws determined using n lgorithm in which microscopic mesures of highest plque density within brin region were verged to produce globl brin estimte of neuritic plque density. The globl neuritic plque density ws ctegorized in the sme mnner s tht for region (Tble 5), where plques were counted on slides with modified Bielschowsky silver stined tissue sections. For purposes of determining the greement between the in-vivo Amyvid imge results nd the post-mortem whole brin myloid neuritic plque density, Amyvid results (negtive/positive) were prespecified to correspond with specific plque density scores, bsed upon modifiction of the Consortium to Estblish Registry for Alzheimer s Disese (CERAD) criteri which use neuritic plque counts s necessry pthologicl feture of AD. Tble 5: Globl nd Regionl Neuritic Plque Density Correltes to Amyvid Imge Results Neuritic Plque Counts CERAD Score Amyvid Imge Result <1 none Negtive 1-5 sprse 6-19 moderte Positive 20+ frequent J of Neuropthology nd Experimentl Neurology 1997; 56(10):1095. Study Two exmined imges only from terminlly ill ptients who hd premortem Amyvid scns nd postmortem brin exmintions to determine truth stndrd. Among the 59 ptients, 35 of whom were lso in Study One, the medin ge ws 83 yers (rnge 47 to 103 yers), hlf were femles nd most were Cucsin (93%). Twenty-nine ptients hd n AD clinicl dignosis, 13 hd nother type of dementing disorder, 12 hd no history of cognitive impirment nd 5 hd MCI. The time intervl between the Amyvid scn nd deth ws less thn one yer for 46 ptients nd between one nd two yers for 13 ptients. Among the subset of ptients who died within one yer of Amyvid scnning ( prespecified outcome), the sensitivity using the mjority interprettion of the reders ws 96% (95% CI: 80% to 100%) nd specificity ws 100% (95% CI: 78% to 100%). With the entire dtset of 59 ptients, the sensitivity using the mjority interprettion of the reders ws 92% (95% CI: 78% to 98%) nd specificity ws 100% (95% CI: 80% to 100%). At utopsy, the globl brin neuritic plque density ctegory (CERAD score, s in Tble 5) ws: frequent n=30; moderte n=9; sprse n=5; nd none n=15. Tbles 6 nd 7 show the Amyvid performnce chrcteristics mong ll the ptients. Among the subset of ptients who died within one yer of Amyvid scnning (n=46; 28 positive nd 18 negtive bsed on histopthology) the medin (nd rnge) of correct red results, flse negtives, nd flse positives were 44 (37 to 45), 1 (0 to 7), nd 1 (0 to 2), respectively, for In-Person Trining (Study Two); nd were 43 (38 to 44), 3 (0 to 7), nd 1 (0 to 2), respectively, for Electronic Medi Trining (Study Three). Tble 6: Amyvid Scn Results by Reder Trining Method mong Autopsied Ptients (n = 59) Sensitivity (%) Specificity (%) Test Performnce In-Person Trining (Study Two) Electronic Medi Trining (Study Three) Medin Rnge mong the 5 reders (69 95) (69 92) Medin Rnge mong the 5 reders (90 100) (90 95) underwent n utopsy (sme ptients s in Study Two) nd provided truth stndrd. Duplicte imges of 33 ptients were included within the totl pool of imges in order to ssess intr-reder imge reproducibility. Among the 151 subjects, the medin ge ws 76 yers (rnge 47 to 103), hlf were femles nd most were Cucsin (93.4%). Performnce chrcteristics for ptients with truth stndrd re shown bove (Tbles 6 nd 7). The mjor reproducibility results re shown in Tble 8 for vrious groups of subjects. Inter-reder reproducibility nlyses for ll imges showed n overll Fleiss kpp sttistic of 0.83 (95% CI: 0.78 to 0.88); the lower bound of the 95% CI exceeded the pre-specified success criterion (95% CI lower bound >0.58). Intr-reder reproducibility nlyses showed tht, between the two redings for ech of the 33 ptients with duplicte imges, one of the five reders hd complete greement for ll 33 ptients, two reders hd discrepnt reds for single ptient, one reder hd discrepnt reds for two ptients nd nother reder hd discrepnt reds for three ptients. Tble 8: Number of Positive Amyvid Scn Results within Study Three Subject Groups nd Reproducibility of Scn Results Among Reders Subject group by cognitive nd truth stndrd (TS, utopsy) sttus Positive Scns, n All subjects with TS, n=59 33 All subjects without TS, n=92 33 AD, n=49 (29 with TS; 20 no TS) MCI, n=57 (5 with TS; 52 no TS) Cognitively norml without TS, n=20 4 Cognitively norml with TS, n = 12 Other (non-ad) dementi with TS, n = Kpp (95% CI) 0.75 (0.67, 0.83) 0.88 (0.82, 0.94) 0.67 (0.58, 0.76) 0.91 (0.83, 0.99) 0.83 (0.69, 0.97) 0.73 (0.55, 0.87) 0.52 (0.35, 0.69) Percent of Scns with Inter-reder Agreement 3 of 5 reders gree 4 of 5 reders gree 5 of 5 reders gree Shown is the medin number of scns interpreted s positive cross the 5 reders for ech subgroup of ptients listed in the first column. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Amyvid is supplied in 10 ml, 30 ml, or 50 ml vils contining 10 ml, ml, or ml, respectively, of cler, colorless solution t strength of MBq/mL ( mci/ml) florbetpir F 18 t EOS. Ech vil contins multiple doses nd is enclosed in shielded continer to minimize externl rdition exposure. 10 ml NDC (IC1200) 30 ml NDC (IC1200) 50 ml NDC (IC1200) 16.2 Storge nd Hndling Store Amyvid t 25ºC (77 F); excursions permitted to 15ºC to 30ºC (59 F to 86 F) [see USP Controlled Room Temperture]. The product does not contin preservtive. Store Amyvid within the originl continer or equivlent rdition shielding. Amyvid must not be diluted. This preprtion is pproved for use by persons under license by the Nucler Regultory Commission or the relevnt regultory uthority of n Agreement Stte. 17 PATIENT COUNSELING INFORMATION Instruct ptients to inform their physicin or helthcre provider if they re pregnnt or brestfeeding. Inform ptients who re brestfeeding to use lternte infnt nutrition sources (e.g., stored brest milk or infnt formul) for 24 hours (>10 hlf-lives of rdioctive decy for the F 18 isotope) fter dministrtion of the drug or void use of the drug. Red Result Tble 7: Amyvid Correct nd Erroneous Scn Results by Reder Trining Method mong Autopsied Ptients In-Person Trining (Study Two) Reder Electronic Medi Trining (Study Three) Reder Correct All Scns with Autopsies (N=59 Flse Negtive ) Flse Positive positive nd 20 negtive bsed on histopthology Study Three included imges from subjects who did not hve truth stndrd (20 helthy volunteers, 52 ptients with mild cognitive impirment, 20 ptients with AD) s well s ll 59 of the ptients who PV 9200 AMP Mrketed by Lilly USA, LLC, Indinpolis, IN 46285, USA Copyright 2012, Eli Lilly nd Compny. All rights reserved. Amyvid (Florbetpir F 18 Injection) for intrvenous use PV 9200 AMP Amyvid (Florbetpir F 18 Injection) for intrvenous use PV 9200 AMP