The Effects of Valbenazine in Participants with Tardive Dyskinesia

SAFETY PROFILE In the extension period, valbenazine was generally well tolerated in a population of LONG-TERM TREATMENT WITH patients with diagnosed schizophrenia, schizoaffective disorder, or mood disorder.8 ONCE-DAILY VALBENAZINE MAY BE AN EFFECTIVE TREATMENT Treatment-emergent adverse events ≥5% in either valbenazine treatment group8,j FOR TD IN ADULTS WITH A • Headache (7.1%) • Dizziness (5.6%) • Urinary tract infection (6.6%) • Suicidal ideation (5.1%) RANGE OF PRESENTATIONS AND • Diarrhea (5.6%) • Depression (4.0%) TREATMENT HISTORIES8 j Combined valbenazine 40 mg and 80 mg once daily.8 • Valbenazine was generally well tolerated through 48 weeks, with There were no clinically important changes in clinical laboratory assessments, sustained TD reductions vital signs, or ECG parameters during the extension or washout periods.8 • TD symptoms tended to return to Psychiatric status generally remained stable during the extension study.8 baseline during the washout period, supporting the maintenance efficacy of ongoing valbenazine treatment LONG-TERM RESULTS

AIMS mean score showed sustained TD reduction AIMS score reduction by ≥50% was generally through Week 488,9 consistent through Week 488

Extension study of valbenazine 40 mg and Percentage of extension study participants valbenazine 80 mg (ITT population)10 with AIMS responsel

1.0 100

90 0.0 -0.1 80 -1.0 -1.3 -1.1 -1.4 70 -1.8 -2.0 -2.3 60 -2.2 -2.9 52.4% -2.5 48.0% -3.0 -2.5 50 46.0% -3.0 P<0.001m -3.5 -3.5 40.0% 41.2% 40 -4.0 -4.2

m 28.8% 28.3% -4.2 -4.8 30 P<0.05 -4.3 -4.4 23.8% 23.4% -5.0 21.0% -5.0 19.7% 20 15.0% -5.5 -6.0 mean score change from BL from change AIMS mean score Patients with AIMS response (%) AIMS response with Patients 10 8.7%

-7.0 0 BL 2 4 6 8 16 32 48 52 n 69 63 70 94 97 81 87 66 75 60 63 60 61 End of WEEK End of End of WEEK 6 n WEEK 8 WEEK 16 WEEK 32 WEEK 48 WEEK 52 DBPC Extension DFWO End of End of End of Placebo Valbenazine 40 mg Valbenazine 80 mg DBPC Extension Washout Re-randomized to valbenazine 40 mg Re-randomized to valbenazine 80 mg

Number of patients Placebo 69 Placebo Re-randomized to VBZ 40 mg VBZ 40 mg 63 59 50 37 34 34 VBZ 40 mg Re-randomized to VBZ 80 mg VBZ 80 mg 70 67 58 50 43 41 VBZ 80 mg Re-randomized 32 29 27 24 24 to VBZ 40 mg Re-randomized 33 31 27 22 22 to VBZ 80 mg

AT 48 WEEKS: ~39% TD reduction with valbenazine 80 mg9,k

k In a post hoc analysis that included patients randomized to valbenazine 80 mg at baseline and those l AIMS response defined as ≥50% improvement from baseline AIMS dyskinesia score.8 who were re-randomized to valbenazine 80 mg at Week 6.9,10 m Not adjusted for multiplicity. Data presented for ITT analysis set. Treatment group comparison based AIMS, Abnormal Involuntary Movement Scale; BL, baseline; DFWO, drug-free washout; on Cochran-Mantel-Haenszel test. P value vs placebo.8,9 iTT, intent-to-treat. n Intent-to-treat population.

During the 4-week washout period, mean AIMS scores generally returned toward baseline.8 • Based on clinical assessment and need, continued valbenazine treatment may be required to maintain TD reductions

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Please see additional Important Safety Information throughout and full Prescribing Information in inside pocket. inside in Information Prescribing full and throughout Information Safety Important additional see Please 21 ercieBocecs n.AlRgt eevd PVZU-52 03/18 CP-VBZ-US-0502 Reserved. Rights All Inc. Biosciences, Neurocrine ©2018

operating a motor vehicle or operating hazardous machinery until they know how they will be affected by INGREZZA. by affected be will they how know they until machinery hazardous operating or vehicle motor a operating

INGREZZA can cause somnolence. Patients should not perform activities requiring mental alertness such as as such alertness mental requiring activities perform not should Patients somnolence. cause can INGREZZA

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WARNINGS & PRECAUTIONS & WARNINGS 10. 10. 9. INGREZZA [package insert]. San Diego, CA: Neurocrine Biosciences, Inc; 2017. Inc; Biosciences, Neurocrine CA: Diego, San insert]. [package INGREZZA Inc. Biosciences, Neurocrine file. on Data

. 2017;78(9):1344-1350. 2017;78(9):1344-1350. . Psychiatry Clin J study. extension 3 KINECT 1-year the of results dyskinesia: tardive with participants in valbenazine of effects

IMPORTANT SAFETY INFORMATION SAFETY IMPORTANT

8. 8. Factor SA, Remington G, Comella CL, et al. The The al. et CL, Comella G, Remington SA, Factor 2017;174(5):476-484. . Psychiatry J Am dyskinesia. tardive for valbenazine of trial placebo-controlled

7. 7. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized, double-blind, double-blind, randomized, 3 phase a 3: KINECT al. et SR, Marder SA, Factor RA, Hauser 1999;39(1):1-16. Res. Schizophr meta-analysis. and review

6. 6. Soares KV, McGrath JJ. The treatment of tardive dyskinesia—a systematic systematic dyskinesia—a tardive of treatment The JJ. McGrath KV, Soares 2014;4:266. (NY). Mov Hyperkinet Other Tremor clinic. disorder INGREZZA® (valbenazine) capsules is indicated for the treatment of adults with tardive dyskinesia. tardive with adults of treatment the for indicated is capsules (valbenazine) INGREZZA®

Tardive syndromes are rarely reversible after discontinuing dopamine receptor blocking agents: experience from a university-based movement movement university-based a from experience agents: blocking receptor dopamine discontinuing after reversible rarely are syndromes Tardive

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5. 5. Zutshi D, Cloud LJ, Factor SA. SA. Factor LJ, Cloud D, Zutshi 2017;78(3):e264-e278. . Psychiatry Clin J meta-analysis. a use: antipsychotic second-generation of period the in

4. 4. Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive dyskinesia prevalence prevalence dyskinesia Tardive CU. Correll JM, Kane CH, Hsieh M, Carbon 1975;41(2):97-104. . Psychopharmalogia chlorpromazine. and loxapine

Important Information Important

et al. Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesia: effects of clozapine, haloperidol, haloperidol, clozapine, of effects dyskinesia: tardive of model a as rat the in receptors dopamine striatal of hypersensitivity Neuroleptic-induced al. et

3. 3. Sayers AC, Bürki HR, Ruch W, W, Ruch HR, Bürki AC, Sayers 2017. 1, February Accessed #c02598-5-1. htm&name=Chapter%205&title=Conventional%20antipsychotics

Cambridge, UK: Cambridge University Press; 2013. http://stahlonline.cambridge.org/essential_4th_chapter.jsf?page=chapter5_introduction. 2013. Press; University Cambridge UK: Cambridge,

2. 2. . 4th ed. ed. 4th . Psychopharmacology Essential Stahl’s SM. Stahl on: Based . Online Psychopharmacology Essential SM. Stahl 2014;11(1):166-176.

References: 1. 1. References: . . Neurotherapeutics disorder. common increasingly an for options therapeutic dyskinesia: Tardive SA. Factor D, Zutshi LJ, Cloud

Supplementary section of article not provided as part of this reprint. this of part as provided not article of section Supplementary a

. 2017;78(9):1344-1350. . Psychiatry Clin J

Factor SA, Remington G, Comella CL, et al. al. et CL, Comella G, Remington SA, Factor

KINECT 3 Extension Study. Extension 3 KINECT

Results of the 1-Year 1-Year the of Results

with Tardive Dyskinesia: Tardive with

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Valbenazine in Participants Participants in Valbenazine

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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch at at MedWatch Visit FDA. the to drugs prescription of effects side negative report to encouraged are You The Effects of of Effects The

vomiting, nausea, and arthralgia. and nausea, vomiting,

≥ 2% and >placebo) include: anticholinergic effects, balance disorders/falls, headache, akathisia, akathisia, headache, disorders/falls, balance effects, anticholinergic include: >placebo) and 2% ( reactions

≥ The most common adverse reaction ( reaction adverse common most The 5% and twice the rate of placebo) is somnolence. Other adverse adverse Other somnolence. is placebo) of rate the twice and 5%

ADVERSE REACTIONS ADVERSE IMPORTANT SAFETY INFORMATION (continued) INFORMATION SAFETY IMPORTANT BACKGROUND SAFETY PROFILE Tardive dyskinesia (TD) is a chronic and potentially irreversible Valbenazine, a novel selective VMAT2 inhibitor, is an In the extension period, valbenazine was generally well tolerated in a population of LONG-TERM TREATMENT WITH drug-induced movement disorder.1 TD is associated with FDA-approved treatment indicated for adults with TD. In a patients with diagnosed schizophrenia, schizoaffective disorder, or mood disorder.8 ONCE-DAILY VALBENAZINE MAY prolonged exposure to dopamine receptor blocking agents pivotal, phase 3 study (KINECT 3), valbenazine 80 mg showed BE AN EFFECTIVE TREATMENT (DRBAs), including first-generation (typical) and significant improvements in TD severity at 6 weeks and had a Treatment-emergent adverse events ≥5% in either valbenazine treatment group8,j 2,3 7 FOR TD IN ADULTS WITH A second-generation (atypical) antipsychotics. generally well-tolerated safety profile. • Headache (7.1%) • Dizziness (5.6%) • Even with the advent of second-generation antipsychotics, VMAT2, vesicular monoamine transporter. • Urinary tract infection (6.6%) • Suicidal ideation (5.1%) RANGE OF PRESENTATIONS AND approximately 20% to 30% of patients with prolonged • Diarrhea (5.6%) • Depression (4.0%) TREATMENT HISTORIES8 4 STUDY OBJECTIVE exposure to DRBAs develop TD j Combined valbenazine 40 mg and 80 mg once daily.8 The KINECT 3 extension period evaluated the long-term safety and • Valbenazine was generally well • Dose reduction or discontinuation of the offending tolerability of once-daily valbenazine (40 mg or 80 mg) in adults with tolerated through 48 weeks, with There were no clinically important changes in clinical laboratory assessments, antipsychotic may not be effective and may exacerbate TD. In addition, long-term effects on TD severity were assessed.8 sustained TD reductions 5,6 vital signs, or ECG parameters during the extension or washout periods.8 the psychiatric disorder • TD symptoms tended to return to METHODOLOGY Psychiatric status generally remained stable during the extension study.8 baseline during the washout period, supporting the maintenance efficacy In the KINECT 3 study, eligible patients received 6 weeks of once-daily valbenazine (40 mg or 80 mg) or placebo.6,b Consenting patients of ongoing valbenazine treatment who completed the 6-week DBPC study were then entered into the blinded extension period and randomized to receive either valbenazine 40 mg or 80 mg once daily. During the first week of the extension period, all randomized patients received valbenazine 40 mg once daily. LONG-TERM RESULTS After the first week, patients who were randomized to receive valbenazine 80 mg once daily had their dose increased.8,c DBPC, double-blind, placebo-controlled. AIMS mean score showed sustained TD reduction AIMS score reduction by ≥50% was generally b In the 6-week study, the primary efficacy endpoint was change in AIMS dyskinesia score (sum of items 1-7) from baseline to week 6 for valbenazine 80 mg once daily vs placebo.7 c Those already receiving either valbenazine dose continued the same dose, while those receiving placebo were randomized (1:1) to valbenazine 40 mg or 80 mg once daily. Participants were allowed 1 dose reduction through Week 488,9 consistent through Week 488 during the study with blinding maintained.8 Extension study of valbenazine 40 mg and Percentage of extension study participants Safety Analyses8,d,e Efficacy Measures Assessed8,e,f valbenazine 80 mg (ITT population)10 with AIMS responsel • Mean Abnormal Involuntary Movement Score (AIMS) • Treatment-emergent adverse events (TEAEs) 1.0 100 • Psychiatric status change from baseline 90 • Treatment-emergent akathisia or parkinsonism • Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) 0.0 -0.1 80 • Emergence of suicidal ideation or behavior • Patient Global Impression of Change (PGIC) -1.0 -1.3 -1.1 -1.4 70 • 12-lead electrocardiogram (ECG) -1.8 -2.0 -2.3 60 • Vital signs and laboratory assessments 52.4% f 8 -2.2 -2.9 Analyzed at each postbaseline visit. -2.5 -2.5 48.0% -3.0 50 m 46.0% d 7,8 -3.0 P<0.001 Safety population. -3.5 -3.5 40.0% 41.2% e All safety data were analyzed descriptively.8 40 -4.0 -4.2

m 28.8% 28.3% -4.2 -4.8 30 P<0.05 -4.3 -4.4 23.8% 23.4% -5.0 21.0% STUDY POPULATION -5.0 19.7% 20 15.0% -5.5 In the extension study, valbenazine was studied in a broad population of patients with various underlying diagnoses and treatment -6.0 mean score change from BL from change AIMS mean score Patients with AIMS response (%) with AIMS response Patients 8.7% regimens. All participants had stable psychiatric status at baseline.8,g 10 -7.0 0 BL 2 4 6 8 16 32 48 52 n 69 63 70 94 97 81 87 66 75 60 63 60 61 7,8 8 Key Inclusion Criteria Select Study Demographics End of WEEK End of End of WEEK 6 n WEEK 8 WEEK 16 WEEK 32 WEEK 48 WEEK 52 DBPC Extension DFWO End of End of End of • Medically stable adults • 198 (96.6%) completers from the DBPC study entered the extension period Placebo Valbenazine 40 mg Valbenazine 80 mg DBPC Extension Washout • 18 to 85 years of age – 124 (62.6%) participants completed the extension periodi Re-randomized to valbenazine 40 mg Re-randomized to valbenazine 80 mg Number of patients – 121 (61.1%) completed washout and week 52 follow-up visit Placebo 69 Placebo Re-randomized to VBZ 40 mg • Participants had one of these diagnoses VBZ 40 mg 63 59 50 37 34 34 VBZ 40 mg Re-randomized to VBZ 80 mg VBZ 80 mg 70 67 58 50 43 41 VBZ 80 mg – Schizophrenia Re-randomized 32 29 27 24 24 • 64.4% had a diagnosis of schizophrenia or schizoaffective disorder to VBZ 40 mg – Schizoaffective disorder • 35.6% had mood disorder Re-randomized 33 31 27 22 22 – Mood disorder to VBZ 80 mg • Diagnosis of DRBA-induced TDh • 71.2% of participants were taking second-generation (atypical) antipsychotics – Moderate to severe TD based on qualitative assessment • 7.9% were taking first-generation (typical) antipsychotics AT 48 WEEKS: ~39% TD reduction with valbenazine 80 mg9,k

g Based on the following accepted measurement scales: Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Young Mania k l 8 7 In a post hoc analysis that included patients randomized to valbenazine 80 mg at baseline and those AIMS response defined as ≥50% improvement from baseline AIMS dyskinesia score. Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale (MADRS). 9,10 m h 6 who were re-randomized to valbenazine 80 mg at Week 6. Not adjusted for multiplicity. Data presented for ITT analysis set. Treatment group comparison based According to the DSM IV, ≥3 months prior to screening. 8,9 i AIMS, Abnormal Involuntary Movement Scale; BL, baseline; DFWO, drug-free washout; on Cochran-Mantel-Haenszel test. P value vs placebo. Treatment-emergent adverse events leading to study discontinuation in >2 participants were somnolence (80 mg once daily, n=3) and suicidal ideation (80 mg once daily, n=1; 40 mg once daily, n=2). n These cases of suicidal ideation or behavior/attempt all resolved with hospitalization/medical management, and were judged by the site investigators as unlikely related to valbenazine.7 iTT, intent-to-treat. Intent-to-treat population. IMPORTANT SAFETY INFORMATION (continued) 8 WARNINGS & PRECAUTIONS (continued) During the 4-week washout period, mean AIMS scores generally returned toward baseline. QT Prolongation • Based on clinical assessment and need, continued valbenazine treatment may be required to maintain TD reductions INGREZZA may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. INGREZZA should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, assess the QT interval before increasing the dosage. FOR MORE INFORMATION, PLEASE VISIT INGREZZAHCP.COM

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Somnolence

. 2017;78(9):1344-1350. 2017;78(9):1344-1350. . Psychiatry Clin J study. extension 3 KINECT 1-year the of results dyskinesia: tardive with participants in valbenazine of effects

IMPORTANT SAFETY INFORMATION SAFETY IMPORTANT

INDICATION & USAGE & INDICATION

5. 5. Zutshi D, Cloud LJ, Factor SA. SA. Factor LJ, Cloud D, Zutshi 2017;78(3):e264-e278. . Psychiatry Clin J meta-analysis. a use: antipsychotic second-generation of period the in

Important Information Important

3. 3. Sayers AC, Bürki HR, Ruch W, W, Ruch HR, Bürki AC, Sayers 2017. 1, February Accessed #c02598-5-1. htm&name=Chapter%205&title=Conventional%20antipsychotics

Cambridge, UK: Cambridge University Press; 2013. http://stahlonline.cambridge.org/essential_4th_chapter.jsf?page=chapter5_introduction. 2013. Press; University Cambridge UK: Cambridge,

2. 2. . 4th ed. ed. 4th . Psychopharmacology Essential Stahl’s SM. Stahl on: Based . Online Psychopharmacology Essential SM. Stahl 2014;11(1):166-176.

References: 1. 1. References: . . Neurotherapeutics disorder. common increasingly an for options therapeutic dyskinesia: Tardive SA. Factor D, Zutshi LJ, Cloud

Supplementary section of article not provided as part of this reprint. this of part as provided not article of section Supplementary a

. 2017;78(9):1344-1350. . Psychiatry Clin J

Factor SA, Remington G, Comella CL, et al. al. et CL, Comella G, Remington SA, Factor

KINECT 3 Extension Study. Extension 3 KINECT

Results of the 1-Year 1-Year the of Results

with Tardive Dyskinesia: Tardive with

Please see inside pocket for full Prescribing Information or visit www.INGREZZAHCP.com. visit or Information Prescribing full for pocket inside see Please

Valbenazine in Participants Participants in Valbenazine

www.fda.gov/medwatch or call 1-800-FDA-1088. call or www.fda.gov/medwatch

vomiting, nausea, and arthralgia. and nausea, vomiting,

≥ 5% and twice the rate of placebo) is somnolence. Other adverse adverse Other somnolence. is placebo) of rate the twice and 5% ( reaction adverse common most The

ADVERSE REACTIONS ADVERSE IMPORTANT SAFETY INFORMATION (continued) INFORMATION SAFETY IMPORTANT SAFETY PROFILE In the extension period, valbenazine was generally well tolerated in a population of LONG-TERM TREATMENT WITH patients with diagnosed schizophrenia, schizoaffective disorder, or mood disorder.8 ONCE-DAILY VALBENAZINE MAY BE AN EFFECTIVE TREATMENT Treatment-emergent adverse events ≥5% in either valbenazine treatment group8,j FOR TD IN ADULTS WITH A • Headache (7.1%) • Dizziness (5.6%) • Urinary tract infection (6.6%) • Suicidal ideation (5.1%) RANGE OF PRESENTATIONS AND • Diarrhea (5.6%) • Depression (4.0%) TREATMENT HISTORIES8 j Combined valbenazine 40 mg and 80 mg once daily.8 • Valbenazine was generally well tolerated through 48 weeks, with There were no clinically important changes in clinical laboratory assessments, sustained TD reductions vital signs, or ECG parameters during the extension or washout periods.8 • TD symptoms tended to return to Psychiatric status generally remained stable during the extension study.8 baseline during the washout period, supporting the maintenance efficacy of ongoing valbenazine treatment LONG-TERM RESULTS

AIMS mean score showed sustained TD reduction AIMS score reduction by ≥50% was generally through Week 488,9 consistent through Week 488

Extension study of valbenazine 40 mg and Percentage of extension study participants valbenazine 80 mg (ITT population)10 with AIMS responsel

1.0 100

90 0.0 -0.1 80 -1.0 -1.3 -1.1 -1.4 70 -1.8 -2.0 -2.3 60 -2.2 -2.9 52.4% -2.5 48.0% -3.0 -2.5 50 46.0% -3.0 P<0.001m -3.5 -3.5 40.0% 41.2% 40 -4.0 -4.2

m 28.8% 28.3% -4.2 -4.8 30 P<0.05 -4.3 -4.4 23.8% 23.4% -5.0 21.0% -5.0 19.7% 20 15.0% -5.5 -6.0 mean score change from BL from change AIMS mean score Patients with AIMS response (%) with AIMS response Patients 10 8.7%

AT 48 WEEKS: ~39% TD reduction with valbenazine 80 mg9,k

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Somnolence

. 2017;78(9):1344-1350. 2017;78(9):1344-1350. . Psychiatry Clin J study. extension 3 KINECT 1-year the of results dyskinesia: tardive with participants in valbenazine of effects

IMPORTANT SAFETY INFORMATION SAFETY IMPORTANT

INDICATION & USAGE & INDICATION

5. 5. Zutshi D, Cloud LJ, Factor SA. SA. Factor LJ, Cloud D, Zutshi 2017;78(3):e264-e278. . Psychiatry Clin J meta-analysis. a use: antipsychotic second-generation of period the in

Important Information Important

3. 3. Sayers AC, Bürki HR, Ruch W, W, Ruch HR, Bürki AC, Sayers 2017. 1, February Accessed #c02598-5-1. htm&name=Chapter%205&title=Conventional%20antipsychotics

Cambridge, UK: Cambridge University Press; 2013. http://stahlonline.cambridge.org/essential_4th_chapter.jsf?page=chapter5_introduction. 2013. Press; University Cambridge UK: Cambridge,

2. 2. . 4th ed. ed. 4th . Psychopharmacology Essential Stahl’s SM. Stahl on: Based . Online Psychopharmacology Essential SM. Stahl 2014;11(1):166-176.

References: 1. 1. References: . . Neurotherapeutics disorder. common increasingly an for options therapeutic dyskinesia: Tardive SA. Factor D, Zutshi LJ, Cloud

Supplementary section of article not provided as part of this reprint. this of part as provided not article of section Supplementary a

. 2017;78(9):1344-1350. . Psychiatry Clin J

Factor SA, Remington G, Comella CL, et al. al. et CL, Comella G, Remington SA, Factor

KINECT 3 Extension Study. Extension 3 KINECT

Results of the 1-Year 1-Year the of Results

with Tardive Dyskinesia: Tardive with

Please see inside pocket for full Prescribing Information or visit www.INGREZZAHCP.com. visit or Information Prescribing full for pocket inside see Please

Valbenazine in Participants Participants in Valbenazine

www.fda.gov/medwatch or call 1-800-FDA-1088. call or www.fda.gov/medwatch

vomiting, nausea, and arthralgia. and nausea, vomiting,

≥ The most common adverse reaction ( reaction adverse common most The 5% and twice the rate of placebo) is somnolence. Other adverse adverse Other somnolence. is placebo) of rate the twice and 5%

ADVERSE REACTIONS ADVERSE IMPORTANT SAFETY INFORMATION (continued) INFORMATION SAFETY IMPORTANT