Opioid Antagonist FDA 승인 ·1 일 1 회 요법 알코올 중독 치료제 1 1 Naltrexone REVIA ®

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 2 Hypothesis Serum and brain levels of β-endorphin increased after alcohol consumption in animals. Serum and brain levels of β-endorphin increased after alcohol consumption in animals. Chronic alcoholics have shown to have significantly decreased plasma and cerebrospinal fluid β-endorphin levels, compared to non-alcohol drinking subject. Chronic alcoholics have shown to have significantly decreased plasma and cerebrospinal fluid β-endorphin levels, compared to non-alcohol drinking subject. Endogeneous opioid Alcohol Opioid like effect

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 3 Alcohol compensation model

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 4 Mechanism of action Abstinence Rates REVIA

FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 5 Opioid receptor antagonism

Opioid Antagonist FDA 승인 ·1 일 1 회 요법 알코올 중독 치료제 6 6 Naltrexone Naltrexone in the treatment of Alcohol Dependence J.R. Volpicelli, A.I. Alterman, M. Hayashida, C.P. O’Brien Arch Gen Psychiatry Vol.43 Jan 1992

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 7 Partial day hospitalization treatment for first month Followed twice per week group therapy for next 11 months Weekly measures for craving, alcohol consumption and mood Monthly safety and laboratory evaluation Study design double-blind, placebo-controlled, randomized trial NTX in the Tx of Alcohol Dependence PlaceboFollow-up Naltrexone HCl 50mg Placebo One week Baseline 12 weeks

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 8 Average No. of Drinking days per weeks in Subjects who sampled alcohol NTX in the Tx of Alcohol Dependence

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 9 NTX in the Tx of Alcohol Dependence Cummulative Relapse Rate

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 10 NTX in the Tx of Alcohol Dependence Alcohol Related Outcomes ParameterPlaceboNaltrexoneP-value % of Drinking Days14%3.6%.05 No. of patients Drinking in the study 20(57%)16(46%)NS Relapse19(54%)8(23%).01 % of patients Drinking that Relapse 95%50%.01 > > > >

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 11 Naltrexone HCl : Appears to be an effective adjunct to the treatment of alcohol dependence Appears to be an effective adjunct to the treatment of alcohol dependence Decreased craving, mean drinking days and relapse rates Decreased craving, mean drinking days and relapse rates Was well tolerated with few side effects and no deleterious effects on mood Was well tolerated with few side effects and no deleterious effects on mood Author’s Conclusion NTX in the Tx of Alcohol Dependence

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 12 Naltrexone vs Acamprosate(1) NTX + ACAM ≥ NTX >> Acamprosate >Placebo Relapse Rate Arch Gen Psychiatry Vol.60 Jan 2003

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 13 Naltrexone vs Acamprosate(2) NTX ≥ NTX + ACAM >> Acamprosate >Placebo Arch Gen Psychiatry Vol.60 Jan 2003 Severity of craving OCDS Score OCDS Score(Obsessive Compulsive Drinking Scale)

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 14 Naltrexone vs Acamprosate(3) Randomized, parallel study, Outcome after 1 year (NTX : 50mg / acamprosate : 1,665~1,998mg) parameterNaltrexone(n=77)Acamprosate(n=80) Composite craving severity score No. of drinks consumed at one time49 Days to first alcohol consumption4439 Days to first relapse6342 No. of days abstinence Alcohol & Alcoholism 2001, 36(5) > > > > >

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 15 Naltrexone vs Acamprosate(4) Naltrexone revealed statistically more effective than Acamprosate in relapse rate Relapse rate Alcohol & Alcoholism 2001, 36(5)419-25

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 16 Naltrexone Tolerability(1) normal normal normal J Clin Pharmacol 1994;34: Chronic administration of naltrexone in doses up to 300 mg/day for periods up to 36months dose not significantly change hepatic function, as measured by SGOT and SGPT levels. GOT, GPT level

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 17 Naltrexone Tolerability(2) LDH level n = 53 n = 53 50mg/day up to 12weeks 50mg/day up to 12weeks Two groups Two groups High baseline High baseline Normal baseline Normal baseline J Clin Pharmacol 1988;28:64-70 Month LDH level was remarkably decreased In both group. Especially, LDH level enter the normal range within only 1 month in high baseline group.

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 18 Naltrexone Tolerability(3) 40 centers 40 centers 25-50mg/day up to 12 weeks 25-50mg/day up to 12 weeks NTX 570 patients NTX 570 patients Liver function test : no difference Liver function test : no difference 3 NTX Tx patients were withdrawn from study due to high level of alanine aminotransferase (indicator of drug induced hepatobilliary injury) 3 NTX Tx patients were withdrawn from study due to high level of alanine aminotransferase (indicator of drug induced hepatobilliary injury) NTX high dose 300mg/day has capacity to cause hepatocellur injury but, NTX dose not to be a hepatotoxin at the recommanded dose NTX high dose 300mg/day has capacity to cause hepatocellur injury but, NTX dose not to be a hepatotoxin at the recommanded dose Arch Gen Psychiatry,1997 Hepatotoxicity

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 19 Naltrexone Tolerability(4) Open label safety study Open label safety study 570 alcoholism patients 570 alcoholism patients New-onset AR occurred in 2% or more of the patients New-onset AR occurred in 2% or more of the patients Nausea10% Headache7% Dizziness4% Nervousness4% Fatigue4% Insomnia3% Vomiting3% Anxiety2% Somnolence2% Adverse Reaction Arch Gen Psychiatry,1997

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 20 Drug abuse and dependence REVIA is a pure opioid antagonist. It does not lead to physical or psychological dependence. Tolerance to the opioid antagonist effect is not known to occur.

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 21 Profile of REVIA Component : Naltrexone HCl 50mg/Tab Component : Naltrexone HCl 50mg/Tab Classification : anti-craving agent(392) Classification : anti-craving agent(392) Dosing : Once daily 50mg Dosing : Once daily 50mg 해독 과정후 Side effect 를 최소화하기 위해 처음 3~4 일간 25mg 을 투여하고, 증량하여 50mg 을 처방 해독 과정후 Side effect 를 최소화하기 위해 처음 3~4 일간 25mg 을 투여하고, 증량하여 50mg 을 처방 복용 기간 : 통상 12 주 복용 기간 : 통상 12 주 Drug Interaction: disulfiram, thioridazine Drug Interaction: disulfiram, thioridazine Contraindication: acute hepatitis, renal failure Contraindication: acute hepatitis, renal failure

REVIA FDA 승인 ·1 일 1 회 요법 알코올중독 치료제 Naltrexone 22 Indication In the treatment of alcohol dependence and For the blockade of the effects of exogenously administered opioids 적정관리 프로그램과 병용하여 알코올의존성 치료 및 외인성 아편류의 효과 차단 REVIA has not been shown to provide any therapeutic benefit excepts as part of an appropriate plan of management for the addictions.