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`ALCOIIULh\1: Cl l\'IC\l. ,\S.:D EXPERIMENT.-',L RL�l,A�CII
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`Vo!. 32. No. 3
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`March 2008
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`Hepatic Safety of Once-Monthly Injectable
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`Extended-Release N altrexone Administered to
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`Actively Drinking Alcoholics
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`Michael R. Lucey, Bernard L. Silverman, Ari llleperuma, and Charles P. O'Brien
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`Background: Hepatoxicity has been reported with or:d naltrexone. Hepatic safety data were
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`exan1ined fro1n a 6-tnonth study evaluating the efficacy and safety of a no\v available cxtended­
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`release fonnulation of naltrexone (XR-NTX) in patients with alcohol dependence.
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`Methods: In all, 624 patients (68°/o 1nale: median age of 44 year�) \vere rando1nly assigned to
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`XR-NTX 380 1ng (11 = 205), XR-NTX 190 mg (11 = 210), or placebo (11 - 209).
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`Results: There were no significant differences in alanine aminotrasferasc. aspartate an1inotrans­
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`ferase. or bilirubin levels betv.'een the study groups at study initiation or at subsequent assess­
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`ments. Gan1ma-gluta1nyltransferase in the XR-NTX 380 n1g group wa� lower compared v,/ith
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`placebo at v.'eeks 4, 8, 12. and 20. Both high ( > 3 ti1nes the upper limit of nonnal) liver chen1istry
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`tests (LCTs) and hepatic-related adverse events were infrequent in all study groups. In patients
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`who were drinking heavily throughout the study, obese subjects. or those taking nonsteroidal
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`anti-inflan11natory drugs. there was no increase in frequency of high LCTs or hepatic-related
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`adverse events in patients receiving XR-NTX (either dose) compared with placebo.
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`Conclusion: Extended-release forn1ulation of naltrexonc docs not appear to be hepatotoxic
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`v.'hen taken at the rccon1mcnded clinical do�es in actively drinking alcohol-dependent patients.
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`Ke)' \\lords: Alcohol Dependence. Liver Injury, Injectable Naltrexone, Rando1ni.1cd Clinical
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`Study, Liver Chen1istry Tests.
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`LCOHOL DEPENDENCE IS a chronic, debilitating
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`the capacity to cause liver damage when taken in excessive
`A
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`doses. that nahrexone is contraindicated in acute hepatitis or
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`disease associated with substantial morbidity and n1or­
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`tality, including hepatic-related disorders (Rehm et al.. 2003).
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`liver failure, and urges caution when it is administered to
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`patients with active liver disease (ReVia, 2006). This was
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`Approximately 10% to 35% of heavy drinkers develop alco­
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`holic hepatitis, and 10 to 20% develop cirrhosis (National
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`based on reports ofhepatotoxicity at high dosages of oral nal­
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`Institute on Alcohol Abuse and Alcoholism, 1998). Pharma­
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`trexone (350 mg/d, which is 7 times the recommended dos­
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`age) in studies with obese patients and those with senile
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`cologic options for the treatment of alcohol dependence
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`dementia (Pfohl et al., 1986). However, in contrast to these
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`include oral naltrexone which, when used in combination \Vith
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`findings, many studies with oral naltrexone have concluded
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`psychosocial intervention, has demonstrated tnodest efficacy
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`that it is safe within the recom,nended dosage range and even
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`in multiple randon1ized clinical studies (Bouza et al., 2004;
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`at higher dosages, as long as the use of over-the-counter non­
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`Roozen et al., 2006). Concern has been raised regarding
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`steroidal anti-inflammatory drugs (NSAID) is restricted (Ball­
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`administration of excessive doses of oral naltrexone or
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`din et al., 2003; Croop et al.. 1997; Gastpar et al., 2002; Kim
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`administration to patients with active liver disease, leading to
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`a boxed warning in relation to hepatotoxicity in the manufac­
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`ct al., 200la, 2006: Verebey and Mule, 1986; Yen et al., 2006).
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`Recently, an injectable formulation of naltrexone
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`turer's package insert. This warning states that naltrexone has
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`(XR-NTX; Vivitrol", Alkermes, Inc., Cambridge, MA, USA)
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`has been developed that provides continuous release of nal­
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`F'ro111 the Section of Gastrocntero/ogy and flepatology, L'11irersit_r
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`trexone for approximately 30 days. with little or no daily fluc­
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`of 1,vr�consin School ((f Medicine and Puhlic Ilea/th r A1 RLJ. lv!adi­
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`tuation (Bartus ct al., 2003; Dunbar et al., 2006; Turncliff
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`son, W'isconsin; A!kennes Inc. ( BLS, Al), Can1hridge, A1assachu­
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`et al., 2005). In a 6-month, randomized, double-blind, study,
`1�/
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`setts; Departnu:nt ,�( Psychiatry. Unfrersity of Pen11syfra11ia .''lchool
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`XR-NTX 380 mg significantly decreased rates of heavy
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`lv!edicine (CPO J, Philadelphia, Pennsy!rania.
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`Recciredf(Jr publication August 1. 2007: accepted lVove1nber 17. 2007.
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`drinking and any drinking (and prolonged abstinence in a
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`Reprint requests: Michuel R. Lucey, l\1/D, Section o/Gastroenter­
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`subset of patients who were initially abstinent) compared to
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`o!ogy and 1/epatology, L,'nfrersit_r of W'isco11si11, 116/516 CSC, 600
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`placebo injection in patients who were receiving counseling
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`Highland A1•cn11e, Afadison, WI 53792-5/24; Fax: (608j 265-5677;
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`for alcohol dependence (Garbutt et al., 2005).
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`E-n1ail: n1rf(i1. 111edicine. H'isc.edu
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`Preliminary analysis of hepatic safety data presented in the
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`Copyrighr © 2008 by the Research Society 011 A!coho!i.wn.
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`1Vo clain1 to original V'.S. govern1ne11t 11·ork.1
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`primary efficacy report on XR-NTX revealed no evidence for
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`hepatotoxicity (Garbutt et al.. 2005). In order to inform the
`DOI: tO. t t t t/j.1530-0277.2007.00593.x
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`498
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`Afco/10{ C/!11 Exp Res. Vol. 32. No 3. 2008: pp 498-504
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`ALKERMES EXHIBIT 2045
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`Page 1 of 7
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`

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`HEPATIC SAFETY OF ONCE-MONTHLY I NJECTABLE NAL TREXONE
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`499
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`than 50°/o of days with �5 drinks per day for men or �4 drinks per
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`clinical use of X R-NTX in alcohol-dependent patients, the
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`day for won1en); (2) obese patients (Body Mass Index > 30 kg/1n�):
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`current article provides a comprehensive analysis of hepatic
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`and (3) patients taking NSAIDs. NSAID use during the 6-month
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`safety from the 6-month large scale, multicenter, placebo-con­
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`treat1nent period was examined using 2 consumption levels defined
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`trolled study of XR-NTX for alcohol dependence, including
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`post-hoc on the basis of patient reports: ( I ) continuous NSAID use;
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`subgroups of patients who were drinking heavily, obese, or
`and (2) any NSAID use.
`using NSA!Ds during the study.
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`MATERIALS AND M ETHODS
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`RESULTS
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`Patient Characterislics and Duration ql Exposure to Study
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`Patient Selection
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`Drug
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`Eligible participants ( 1 8 years or older) were required to meet a
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`current diagnosis of alcohol dependence, defined by the Diagnostic
`In all, 624 patients had at least I injection of XR-NTX and
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`Disorders. Fourth Edition (A1nerican
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`and Statistical lt1a1111al (?f'A!ental
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`comprised the intent-to-treat population. The 3 study groups
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`Psychiatric Association, 1 994). and abo report a 1ninimum of 2 epi­
`(XR-NTX 380 mg, 11 � 205; XR-NTX 1 90 mg, 11 � 2 1 0;
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`sodes of heavy drinking (�5 standard drinks/d for men and �4 stan­
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`placebo, n = 209) were sin1ilar in terms of baseline demo­
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`dard drinks/d for \\'Omen) per \\.'eek during the 30 days prior to
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`screening. Patients were excluded if they had any clinically significant
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`graphic, clinical characteristics, and baseline LCT levels
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`medical condition that might adversely affect safety or study partici­
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`(Table I ), Similar percentages of patients in the 3 study
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`pation; major depression \vith suicidal ideation, psychosis, or bipolar
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`groups received all 6 injections (63°1,, for XR-NTX 380 mg:
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`disorder: dependence on benzodiazepines, opiates. or cocaine \Vithin
`65% for XR-NTX 190 mg: 64% for placebo) during the
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`the past year; or n1ore than 7 days of inpatient treatment for sub­
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`6-month treatment period, As specified by the study selection
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`stance abuse during the 30 days prior to screening. Exclusion criteria
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`also included evidence of liver failure. and/or alanine a1ninotransfer­
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`criteria, all patients had either normal (70% ) or elevated
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`ase (ALT) or aspartate a1ninotransfcrasc (AST) levels greater than 3
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`(30%) levels of A LT and AST. Four patients had elevated
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`tin1cs the upper limit of norn1al ( > 3xlJLN).
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`baseline levels of total bilirubin; all others had values in the
`Most �ubjects (48.6(Xi) in the randon1izcd sample were recruited
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`normal range, As for GGT levels at baseline, 64% of patients
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`and enrolled at a clinical addiction treatment center: 34.0°/o enrolled
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`had nom1al levels, 28% elevated, and 8% high, The baseline
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`at a research center: and 1 7.So/o enrolled at a setting that was a con1-
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`bination clinical addiction and research center. All patients \Vho par­
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`demographic and clinical characteristics of the heavy drink­
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`ticipated in the trial provided written, informed consent. and the
`ing, obese, and noncontinuous NSAID-taking subgroups
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`protocol was approved by the respective institutional review boards
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`(values \Vere similar for the s1naller continuously using
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`at the participating clinical sites.
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`NSAID group) were also similar for tlie XR-NTX 380 mg,
`X R-NTX 190 mg, and placebo groups (Table 2), Postbaseline
`Treatn1ent
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`laboratory assessn1ent of hepatic function was available for
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`Patients \Vere rando111ly assigned to 6 n1onths of trcatn1ent \Vith
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`1 93 (94%) patients who received XR-NTX 380 mg, 193
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`XR-NTX 380 mg, XR-NTX 1 90 mg, or placebo, XR-NTX was
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`(92% ) patients who received XR-NTX 1 90 mg, and 1 98
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`given every 4 \Vecks as an intramuscular gluteal injection, alternating
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`(95'% ) patients who received placebo, Only 2 patients with­
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`sides \Vith each visit. Patients \Vere not required to he abstinent at the
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`to vn if they continued time of initial injection and were not V·iithdra\
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`drew from the study due to hepatic-related adverse events.
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`use alcohol. In addition to receiving study medication, patients \\.'ere
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`also provided with psychosocial support \\'ith the BiopsychosociaL
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`Report. Empathy, Needs. I)irect advice, and Assessn1ent model at
`Liver (�he1nistry Test Results
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`study visits (Volpicelli et al., 200 1 ). No specific recon1111endations
`There were no significant differences (by Kruskal-Wallis
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`v.1ere communicated to the patients about NSAID use. The following
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`1nedications \Vere not permitted during the study unless required to
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`test) bet\\'een the study groups at any study visit on median
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`treat an adverse event, when no other alternative \\'as available:
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`levels of ALT. AST, or total bilirubin, For serum GGT levels,
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`aca,nprosate, buprenorphine. disulfiram. lcvon1ethadyl acetate/1.-,:x­
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`lower values were apparent for the XR-NTX 380 mg group
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`acetyhnethadol (LAAM), 111ethadone, oral naltrcxone, phenelzine.
`at weeks 4, 8, 1 2, and 20 (p < 0,05) and the XR-NTX
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`selegiline, and tranylcyprominc.
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`1 90 mg group at weeks 8 and 1 2, \Vhich reached statistical sig­
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`nificance (p < 0.05) compared with placebo.
`Asses.wnent of' Hepath· Health
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`The percentage of patients with any high postbaseline
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`Patients \\'ere asked about all concomitant medications taken dur­
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`(treat1nent-e1nergent) enzyme levels was low and was not sig­
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`ing the study, including but not li1nited to NSAIDs. Liver health was
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`nificantly different (by Fisher's exact test) for X R-NTX
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`assessed every 4 weeks for the 6-1nonth treatment period by measur­
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`ing liver chemistry test ( LCT) levels of the IOllO\\.'ing enzyn1es: ALT,
`380 mg (9% [ 1 7/193]) and XR-NTX 1 90 mg [ 1 2% (24/193)]
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`AST, gan1ma-glutan1yl transferasc (GGT), and total bilirubin. Safety
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`compared with placebo [15'Yo (29/198)] (Table 3), Rates for
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`data collected during the study included adverse events as reported
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`high levels of specific LCTs (ALT, AST, GGT, and total bili­
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`by patients or noted by study staff, physical examination results
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`rubin) were also low and not significantly diiferent a1nong the
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`measurements. (including vital signs), and clinical laboratory
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`study groups, Specifically, the percent of patients with a high
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`Results of LCTs \\'ere classified as nonnal. elevated (any increase
`above the ULN but belo\v 3xULN), or high ( > 3xULN). Exan1ina­
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`( >3xULN) ALT value at any time during the 6-month treat­
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`tion of study group diO'erences in enzyme levels and adverse events
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`ment period was 3% for XR-NTX 380 mg, I % for XR-NTX
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`were also conducted \\'ithin 3 subgroups: ( 1 ) those patients contin­
`1 90 mg, and 3 % for placebo, For AST, the rates of high
`
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`uing to drink alcohol at a high rate throughout the study (greater
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`J
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`Page 2 of 7
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`500
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`LUCEY ET AL.
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`Table 1. Baseline Demographic and Clinical Characteristics and Liver Chemistry Test (LCT) Results tor the lntent·to-Treat Population
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`Baseline characteristics
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`XR-NTX 380 mg (n = 205) XR-NTX 190 mg (n = 210) Placebo (n = 209)
`
`Male, n (0/o)
`Age in years, median
`Race, n (0/o)
`White
`Black
`Hispanic
`Number of heavy drinking days within the past 30 days, median
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`
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`Number of drinking days within the last 30 days, median
`Body weight (kg), mean (SD)
`LCT s, median
`ALT
`AST
`GGT
`Total bilirubin
`
`138 (67%)
`45.0
`
`142 (67%)
`44.0
`
`143 (68%)
`44.0
`
`172 (84%)
`16 (8%)
`10 (5%)
`19.0
`25.0
`84.3 (21)
`
`169 (80%)
`17 (8%)
`15 (7%)
`19.0
`25.0
`82.8 (20)
`
`180 (86%)
`17 (8%)
`7 (3%)
`20.0
`24.0
`81.9 (17)
`
`27.0
`26.0
`41.0
`0.50
`
`28.0
`27.0
`43.0
`0.50
`
`27.5
`26.0
`42.0
`0.50
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`Heavy drinking defined as ;::,:5 drinks/d for men and ;::,:4 for women.
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`transferase.
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`XR·NTX, extended·release formulation of naltrexone; ALT, alanine aminotranslerase; AST, aspartate aminotransferase; GGT, gamma-glutamyl
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`Table 2. Baseline Demographic and Clinical Characteristics and Liver Chemistry Test (LCT) Results for Subgroup Populations
`
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`Heavy drinking patients Obese patients
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`NSAID-taking patients
`
`XR-NTX XR-NTX
`XR-NTX XR-NTX
`XR-NTX XR-NTX
`380 mg 190 mg Placebo 380 mg 190 mg Placebo 380 mg 190 mg Placebo
`Characteristic (n = 33) (n= 47) (n = 52) (n = 58) (n = 45) (n = 50) (n = 62) (n = 50) (n = 52)
`Male, n (0/o)
`18 (55%) 33 (70%) 37 (71%) 44 (76%) 35 (78%) 36 (72%) 44 (71%) 29 (58%) 28 (54%)
`Age in years, median 47.0 46.0 44.0 45.0 44.0 47.0 47.5 40.5 44.0
`Race, n (0/o)
`29 (88%) 43 (92°/o)50 (96%) 49 (85%) 32 (71%) 42 (84°/o) 52 (84%) 36 (72%) 49 (94%)
`White
`Black
`2 (6%) 2 (4%) 2 (4%) 5 (9%) 5 (11%) 3 (6%) 5 (8%) 6 (12%) 2 (4%)
`2 (6%) 2 (4°/o) 0 (0%) 4 (7%) 4 (9%) 3 (6o/o) 2 (3%) 5 (10%) 1 (2°/o)
`Other
`days 29.0 27.0 27.5 18.5 20.0 20.5 17.5 16.5 14.0
`Number of heavy drinking
`
`within the past 30 days, median
`
`Number of drinking days within 30.0 30.0 29.0 21.5 26.0 25.5 27.5 22.0 19.5
`the last 30 days, median
`Body weight (kg), mean (SD) 87.1 (23) 83.1 (15) 83.6 (16) 106.4 (16) 110.0 (18) 102.0 (13) 86.0 (18) 82.1 (24) 79.7 (16)
`LCTs, median
`ALT
`AST
`GGT
`Total bilirubin
`
`27.0 31.0 34.5 32.5 38.0 37.0 30.0 27.5 24.5
`28.0 30.0 31.0 27.0 30.0 28.0 30.0 27.5 24.0
`62.0 54.0 63.0 46.0 72.0 59.5 44.0 40.5 32.0
`0.40 0.60 0.50 0.50 0.50 0.50 0.50 0.50 0.50
`
`
`
`Heavy drinking defined as :;::,:5 drinks/d for men and ;::,:4 for women. Nonsteroidal anti-inflammatory drugs (NSAID)-taking subgroup includes
`
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`
`
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`those patients taking NSAIDs at any time during the treatment period, but not continuously throughout.
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`
`
`
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`transferase.
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`XR-NTX, extended-release formulation of naltrexone; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl
`
`values were 5, 5, and 6% (380 mg, 190 mg, and placebo,
`
`ences among the study groups in the cumulative proportion
`
`
`
`respectively). For GGT, the rates of high values were 7, 11,
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`
`of patients having any specific LCT result classified as high,
`and 11% for the XR-NTX 380 mg, XT-NTX 190 mg, and
`
`
`
`as determined by log-rank tests of the Kaplan-Meier curves
`
`placebo groups. respectively. For all of the LCTs, the percent­
`
`
`
`(Table 5). There was no evidence of increased rates of high
`
`
`age of patients in the placebo group with high or elevated
`
`
`
`values of LCTs during the first few weeks of treatment with
`
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`(higher than the ULN but < 3xULN) hepatic enzyme levels
`XR-NTX.
`
`
`was numerically greater than in the XR-NTX 380 mg group
`Of the patients who had normal ALT values at baseline,
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`
`
`(Table 3).
`
`
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`the percentages that had elevated and high values, respec­
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`A similar, albeit small, percentage of patients whose LCT
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`tively, at the end of the study were 11% (16/151) and 0%
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`values were elevated (and high for GGT) at baseline moved
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`(XR-NTX 380 mg), 10% (15/148) and 0% (XR-NTX
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`
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`into normal range during the course of the study: data for the
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`190 mg), and 7% (10/150), 1% (1/150) (placebo). For AST,
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`XR-NTX 380 mg, XR-NTX 190 mg, and placebo groups
`
`
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`the percentages with normal values at baseline that had ele­
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`were respectively 5, 2, and 2% (ALT); 7, 6, and 5% (AST); 8,
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`
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`vated and high values at final visit were 6% (9/147) and 1 %
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`7, and 7% (GGT) (Table 4). There were no significant differ-
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`(2/147) (XR-NTX 380 mg), 7% (10/144) and 0% (XR-NTX
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`Page 3 of 7
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`

`

`NALTREXONE
`INJECTABLE
`HEPATIC SAFETY OF ONCE-MONTHLY
`
`501
`
`Tests
`in Liver Chemistry
`Abnonnalities
`Table 3. Treatment-Emergent
`Abnonnalities
`in Liver
`of Treatment-Emergent
`Table 5. Time of Onset
`Events During 6 Months of Treatment
`Adverse
`(LCTs) and Hepatic
`Tests (LCTs)
`Chemistry
`
`LCT
`
`XR-NTX XR-NTX
`380 mg
`190 mg
`Placebo
`(n = 205) (n = 210) (n = 209)
`LCT
`
`XR-NTX XR-NTX
`380 mg 190 mg Placebo
`(n = 205) (n = 210) (n = 209)
`
`15 (8%)
`0
`
`14 (7%)
`0
`
`LCT
`
`n (%)
`LCTs, total,
`Any LCT, n {0/o) <3xULN 196 (96%) 190(91%) 191 (91%)
`Elevated 69 (36%) 89 (46%) 79 (40%)
`rate of abnormality,
`n (0/o)
`Cumulative
`High
`24 (12%) 29 (15%)
`17 (9%)
`Week4
`3 (2%) 3 (2%) 5 (3%)
`ALT, n (%)
`Week8
`3 (2%) 8 (5%) 6 (3%)
`Elevated 55 (29%) 60 (31%) 64 (32%)
`Week 12
`8 (5%) 9 (6%) 9 (5%)
`High
`2 (1%)
`6 (3%)
`5 (3%)
`Week 16
`8 (5°/o) 10 (6%) 12 {Bo/o)
`AST, n (%)
`8 (5%) 10 (6%) 13 (8%)
`Week 20
`Elevated 44 (23%) 60 (31%) 70 (35%)
`Week 24
`10 (7%) 10 (6%) 14 (9%)
`9 (5%)
`12 (6%)
`High
`ALT, n (0/o) <3xULN 205 (100%) 210 (100%) 208 (100%)
`9 (5%)
`GGT, n (%)
`of abnormality,
`n (o/o)
`Cumulative rate
`Elevated 40 (21%) 61 (32%) 58 (29%)
`1 {<1°/o) 1 (<1%) 1 (<1%)
`Week 4
`High
`22(11%) 22(11%)
`3 (2°/o) 1 (<1°/o) 1 (<1%)
`13 (7%)
`Week B
`Bilirubln,
`n (0/o)
`Week 12
`5 (3%) 1 (<1%) 3 (2%)
`Week 16
`Elevated
`5 (3%) 1 (<1%) 5 (3%)
`7 (4%)
`High
`5 (3%) 2 (1%) 6 (4%)
`Week 20
`0
`n (0/o)
`events,
`adverse
`Hepatic
`Week 24
`5 (3%) 2 (1%) 6 (4%)
`Hepatomegaly 1 (<1°/o) 1 (<1°/o) 0
`AST, n (0/o) <3xULN 205 (100%) 209 (100%) 208 (100%)
`Cholelithiasis
`n (0/o)
`0
`rate of abnormality,
`Cumulative
`1 (<1%) 0
`1 (<1°/o) 1 (<1%) 0
`Hepatitis
`C
`1 (<1°/o) 3 (2%) 5 (3%)
`Week4
`Weeks
`4 (2%) 8 (4%) 6 (3%)
`6 (4%) 8 (4%) 9 (5%)
`Week 12
`as above upper limit normal range (ULN)
`defined
`baseline
`Elevated
`6 (4°/o) 8 (4%) 11 (6%)
`Week 16
`as >3xULN.
`but �3xULN; high defined
`Week 20
`7 (4%) 9 (5°/o) 11 (6%)
`ALT, alanine
`of naltrexone;
`formulation
`XR-NTX, extended-release
`9 (6%) 9 (5%) 12 (7°/o)
`Week 24
`aminotransferase;
`GGT, gamma-
`AST, aspartate
`aminotransferase;
`GGT, n (0/o) <3xULN 196 (96%) 190 (91%) 191 (91%)
`transfera
`se.
`glutamyl
`rate of abnormality,
`n (0/o)
`Cumulative
`2 (1%) 3 (2%) 3 (2%)
`Week4
`3 (2%) 6 (4%) 3 (2%)
`Week 8
`5 (3%) 7 (4%) 4 (2%)
`Week 12
`at Final Visit Among Patients
`Table 4. Liver Chemistry Test (LCT) Results
`Week 16
`5 (3%) 8 (5%) 6 (4%)
`Levels at Baseline
`With Elevated
`5 (3°/o) 8 (5%) 6 (4%)
`Week 20
`6 (4%) 8 (5%) 7 (5%)
`Week 24
`XR-NTX 380 mg XR-NTX 190 mg Placebo
`n (0/o) <3xULN 205 (100%) 210 (100%) 208 (100%)
`Total Bilirubin,
`rate of abnormality,
`n (0/o)
`Cumulative
`ALT, n (0/o)
`Week 4
`0
`Normal 18 (42.9%) 27 (60.0%) 22 (46.8%)
`Week B
`0
`Elevated 22 (52.4%) 17 (37.8%) 24 (51.1%)
`Week 12
`0
`2 (4.8%) 1 (2.2%) 1 (2.1%)
`High
`0
`Week 16
`AST, n (0/o)
`Week 20
`0
`Normal 23 (51.1%) 31 (64.6%) 16 (38.1%)
`Week 24
`0
`Elevated 19 (42.2%) 14 (29.2%) 24 (57.1%)
`3 (6.7%) 3 (6.3%) 2 (4.8%)
`High
`GGT, n (%)
`number of patients
`of cumulative
`Rates are Kaplan-Meier estimates
`Normal 18 (34.0%) 19 (35.2°/o 22 (38.6%)
`designated
`value >3xULN on or before the
`who had a laboratory
`Elevated 31 (58.5%) 31 (57.4%) 31 (54.4%)
`week.
`4 (7.5%) 4 (7.4°/o) 4 (7.0%)
`High
`ALT, alanine
`of naltrexone;
`formulation
`XR-NTX, extended-release
`Bilirubin,
`n (0/o)
`AST, aspartate aminotransferase;
`GGT, gamma-
`aminotransferase;
`Normal None elevated 1 (33.3%) 1 (100%)
`transferase.
`glutamyl
`2 (66.7%) 0
`Elevated
`0
`0
`High
`
`0
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`
`in the
`4% (7/190)
`in the XR-NTX 380 mg group,
`I% (2/193)
`as above upper limit normal range (ULN)
`defined
`baseline
`Elevated
`for the per­
`as >3xULN. The denominators
`but �3xULN; high defined
`in the placebo
`XR-NTX 190 mg group, and 3% (5/196)
`are the numbers with an elevated baseline
`value in that
`centages
`values at final visit (none had high
`group had elevated
`study group.
`of naltrexone; ALT, alanine
`formulation
`XR-NTX, extended-release
`values).
`se; GGT, gamma­
`aminotransfera
`AST, aspartate
`aminotransferase;
`transferase.
`glutamyl
`
`Events
`Adrerse
`Hepath·
`Reported
`
`were well tolerated and
`rates
`all study medications
`Overall,
`190 mg), and 12°1,, (18/155),
`I% (2/155) (placebo).
`For
`3). In the
`were low (Table
`events
`of hepatic-related
`adverse
`at baseline
`that
`with normal values
`GGT, the percentages
`with hepatomeg­
`there was I patient
`XR-NTX 380 mg group,
`at the end of the study were 3%
`and high values
`had elevated
`study injec­
`of the first
`aly with an onset 182 days after receipt
`380 mg), 7% (9/121)
`and
`I% (1/132) (XR-NTX
`(3/132) and
`C infection
`with hepatitis
`diagnosed
`tion, and 1 patient
`0% (placebo).
`Of
`0% (XR-NTX 190 mg), and 10% (12/124),
`In the XR-NTX
`(71 days after first dose of medication).
`at baseline,
`of total bilirubin
`with normal levels
`the patients
`
`j
`
`Page 4 of 7
`
`

`

`502
`
`LUCEY ET AL.
`
`DISCUSSION
`
`
`Suhgroup
`
`LTsing Patients
`
`190 mg group. there was also I patient diagnosed with hepa­
`
`
`
`
`
`
`tomegaly (onset 168 days after first study injection) and 1
`Alcohol dependence is a chronic and debilitating disease,
`
`
`
`
`
`
`with hepatitis C infection (64 days after first study injection).
`
`
`
`wherein approximately 10 to 35% of heavy drinkers develop
`
`
`No patients in the placebo group had any hepatic-related
`
`
`
`
`alcoholic hepatitis, and IO to 20% develop cirrhosis (National
`y colic),
`
`
`
`
`adverse events. One serious adverse event (biliar
`
`
`
`
`Institute on Alcohol Abuse and Alcoholism, 1998). Many
`judged as not related
`
`
`to study drug, was reported during the
`
`
`
`
`
`factors including alcohol consumption. gender, comorbid
`
`
`
`6-month treatment period in the XR-NTX 190 group.
`
`
`
`
`diseases and host susceptibility determine whether alcohol­
`
`
`
`dependent individuals progress to significant
`liver injury
`Analys es: Hem'_l' Drinking, Obese, and NSAID­
`
`
`(Tome and Lucey, 2004). Among these factors. there is a
`
`
`
`
`dose-response curve linking alcohol dose to incidence of cir­
`
`
`
`rhosis (Bellentani et al.. 1997). Consequently, therapies which
`
`In all. 126 (20%) patients continued to drink alcohol
`
`
`
`
`
`promote either abstinence from or at least reduced intake of
`
`
`
`heavily throughout the study and had postbaseline assess­
`ments of LCTs [XR-NTX 380 mg. 11 � 33 of 205 (16°/.,);
`
`
`
`
`
`alcohol are urgently needed. Antagonism of opiate receptors
`
`
`
`by naltrexone has been shown to reduce drinking in alcohol­
`
`XR-NTX 190 mg. 11 � 44 of 210 (21 %); placebo. n � 49
`
`
`
`
`dependent patients. However, the utility of this oral naltrex­
`
`
`
`of 209 (23%)]. Comparison of the subgroups in rates of
`
`by difficulties in maintainin
`
`
`
`high ( > 3xULN) values of post baseline LCTs revealed no
`one has been compromised
`g daily
`
`
`
`
`significant differences overall or for specific LCTs. The per­
`
`
`
`
`dosing, by fluctuating naltrexone blood levels, and by con­
`on any LCT were 12°/i,
`cerns about hepatotoxicit
`
`cent of patients \Vith high values
`
`
`y in relation to the "black box warn­
`
`
`
`ing"". Thus. XR-NTX offers potential advantages by
`
`
`
`(4/33). 25% (11/44). and 22% (11/49) for the 380 mg.
`
`
`
`190 mg. and placebo groups, respectively. Rates for high
`
`
`
`alleviating the patient burden of daily dosing, and reduced
`
`
`total dosage which 1nay lead to better medication adherence.
`
`
`individual LCTs were as follows: ALT [380 mg: 0%
`
`
`
`
`(0/33); 190 mg: 2% (1/44), placebo: 6% (3/49)]. AST [3%
`
`
`
`reduced risk of toxicity and improved outcomes.
`
`
`
`In order to be clinically acceptable, it is necessary to deter­
`
`
`
`
`(1/33). 11 % (5/44), 10% (5/49)]. GGT [9% (3/33). 21 %
`
`
`
`20% (10/49)]. and total bilirubin [3% (1/33). 0%
`
`
`
`mine whether XR-NTX is safe, particularly in actively drink­
`(9/44).
`
`
`
`
`
`ing alcoholic subjects. A previous publication reported that
`
`(0/44). 4% (2/49)].
`
`
`One hundred and fifty three (25%) obese patients partici­
`
`nausea, fatigue, decreased
`
`
`appetite, dizziness, and injection
`
`
`pated in the study and had postbaseline assessments of LCTs.
`
`site pain occurred significantly
`
`
`111ore frequently in XR-NTX
`
`
`
`
`380 mg-treated patients compared to placebo-treated patients
`
`
`
`There were no significant ditTerences between the study
`
`
`
`
`(Garbutt et al.. 2005). In regard to hepatotoxicity, there had
`
`
`
`
`groups with regard to the percentage of patients with high lev­
`
`
`
`
`been some reports that treattnent of alcohol dependence with
`
`
`
`els of ALT [3% (2/58). 2% (1/45). and 4% (2/50). for XR­
`
`
`
`oral naltrexone is associated with liver-related problems
`
`
`NTX 380 mg. XR-NTX 190 mg. and placebo groups. respec­
`
`more likely, however, tol­
`
`
`
`
`tively]. AST [3% (2/58). 9'Yo (4/45), and 6% (3/50)]. or total
`
`(excessive doses in obese patients);
`
`bilirubin (0% for all 3 groups).
`
`
`
`
`erability issues arise from the ongoing alcohol use. Pilot stud­
`
`
`
`ies of injectable naltrexone have been encouraging in regard
`
`
`Among patients taking NSA!Ds continuously (11 � 81;
`
`
`
`to hepatic safety. A small (n � 12) open-label. nonplacebo­
`
`
`
`13%), there was no significant difference between the study
`
`
`
`
`controlled pharmacokinetic study provided preliminary hepa­
`
`groups in the overall rate of any LCT during the 6-month
`
`
`study period. or in the rates of specific LCTs, in the high
`
`
`tic safety data regarding a single dose of I 90 mg of XR-NTX
`
`range. Rates for any high laborator
`
`
`
`
`enzy1nes were y n1eaningful changes in hepatic
`
`
`y tests were similar for
`(no clinicall
`
`XR-NTX 380 mg [17% (5/29)]. XR-NTX 190 mg [5%
`
`
`
`found among subjects with mild or moderate hepatic impair­
`
`
`
`(1/20)] and placebo [25% (32/52)]. There were also no signifi­
`
`
`
`
`ment) (Turncliff et al., 2005). Additional preliminary hepatic
`
`cant study group differences in the rates of hepatic-related
`
`
`
`safety data on XR-NTX was reported in the context of a
`
`
`safety study in which 25 alcohol-dependent patients received
`
`
`
`
`
`adverse events within the subgroup of patients using NSAIDs
`
`
`400 mg of XR-NTX and 5 received placebo in 4 monthly
`
`
`continuously. For patients (11 � 164; 26%) using NSAIDs at
`
`
`some point during the treatment period, but not continuously.
`
`
`
`
`to injections ( 1 severe event of hepatomegaly was determined
`
`
`
`there were also no significant differences between the study
`
`
`
`be unrelated to the use of study medication) (Johnson et al.,
`
`
`
`
`groups in rates of LCT results (overall or specific tests) classi­
`
`
`
`
`2004). Another placebo-controlled study of a different inject­
`
`
`fied as high, or in hepatic-related adverse events.
`
`
`
`
`able version of naltrexone reported no difTerence in GGT lev­
`
`
`
`Few hepatic-related adverse events and serious adverse
`
`
`
`
`els for extended-release naltrexone compared to placebo over
`
`
`There by patients in these subgroups.
`
`events were reported
`
`
`3 months of treatment (Kranzler et al., 2004).
`
`
`
`were 2 cases of hepatitis C infection within the obese sub­
`
`
`
`In the present analysis, the effects of XR-NTX on hepatic
`
`group: I case in the XR-NTX 380 mg group and 1 case in the
`
`
`
`
`function in patients with alcohol dependence were investi­
`
`
`XR-NTX 190 mg group (this latter case also was in the heavy
`
`
`
`gated in this 6-month, randomized, double-blind, placebo­
`
`
`
`adverse event (described subgroup). The only serious
`drinking
`
`controlled study. The LCTs (ALT, AST. GGT. total
`
`
`
`above), occurred in an obese \Voman receiving XR-NTX
`
`
`
`
`bilirubin) suggest that there is no evidence of hepatic dysfunc­
`
`190 mg and taking an NSAID intermittently.
`tion with use of XR-NTX at the U.S. Food and Drug
`
`Page 5 of 7
`
`

`

`
`
`HEPATIC SAFETY OF ONCE-MONTHLY INJECTABLE NALTREXONE
`
`
`
`503
`
`ommended dosages of XR-NTX on liver function is not
`
`
`
`Administration-approved dose (380 mg), compared with
`
`
`
`
`
`
`placebo. There was no evidence of increased rates of high
`known.
`
`
`( >3xULN) values of LCTs during the first few weeks of
`Caution is warranted lest data fro1n the present study be
`
`
`
`
`
`treatment with XR-NTX. Rates of hepatic-related adverse
`
`
`
`
`extrapolated to subjects outside the entry criteria. We recog­
`
`
`events were low and not significantly different between
`
`
`nize that the exclusion of individuals dependent on opiates,
`
`
`cocaine, or benzodiazepines, or those unable to comply with
`
`
`XR-NTX (either dose) and placebo. The lack of hepatoxicity
`
`
`
`found in the current study is consistent with studies evaluating
`
`
`
`the rigorous study protocol will limit the generalizability of
`
`
`
`oral naltrexone administered at recommended doses to appro­
`
`
`
`the findings. Beyond these exclusion criteria the sample was
`
`
`
`priately selected patients (Anton et al., 2006; Chick et al.,
`
`
`
`broadly representative of alcohol-dependent individuals.
`
`
`Although the study had no upper age limit, no patients above
`
`
`2000; O'Malley et al., 1992; Volpicelli et al., 1992).
`
`Values of GGT were significantly lower in the XR-NTX
`
`
`
`
`age 80 years participated, and therefore the hepatic effects of
`
`
`
`
`380 mg group during the study compared with placebo. This
`
`
`XR-NTX in the very old remains unknown. Finally, the con­
`
`
`beneficial effect of XR-NTX 380 mg is likely to be due to the
`
`sequences for liver health of use of XR-NTX beyond
`
`
`
`promotion of abstinence and reduced drinking, and in partic­
`6 months were not examined.
`
`
`ular reduction of heavy drinking, that has been demonstrated
`This study has important clinical implications. Most indi­
`
`
`
`
`
`viduals presenting for treatment for alcohol depen­
`
`with XR-NTX 380 mg (Garbutt et al., 2005).
`
`
`Although XR-NTX has been shown to be effective as a
`
`
`
`dence/abuse have some degree of hepatic abnormality as
`
`
`
`
`
`modifier of harmful drinking (Garbutt et al., 2005), some
`
`
`
`measured by LCTs. Clinicians have been reluctant to pre­
`
`
`
`
`patients will continue to use alcohol, at times heavily, while
`
`
`
`
`scribe naltrexone for such patients because of the black box
`
`
`on this medication. A key finding of the present study is that
`
`
`
`
`warning associated with the oral formulation. The results of
`
`
`the administration of XR-NTX to the subgroup of patients
`
`
`this study support the use of XR-NTX despite the mild to
`
`
`
`who continued to drink heavily throughout the study was not
`
`
`moderately elevated LCTs.
`
`
`
`
`associated with increased levels of serun1 markers of liver
`
`
`injury. These data suggest that XR-NTX does not interact
`
`
`
`
`with alcohol, even when consumed in excessive amounts, to
`Funding for this clinical study and publication was pro­
`
`
`
`
`promote hepatoxicity.
`
`
`Also of importance was the lack of increased rates of treat­
`
`
`vided by Alkermes, Inc., Cambridge, MA and Cephalon,
`
`
`
`ment-emergent LCTs following XR-NTX (at either dosage)
`
`Inc., Frazer, PA, who market XR-NTX. We wish to thank
`
`
`
`
`compared to placebo in patients who were obese. These data
`
`
`
`the following investigators who participated in the study:
`
`
`Robert Anthenelli, MD, Cincinnati, OH; Louise Beckett,
`
`
`
`in obese of oral naltrexone are consistent with early studies
`
`
`MD, Oklahoma City, OK; Michael Bohn, MD, Middleton,
`
`patients (Pfohl et al., 1986).
`
`WI; Paul Casadonte, MD, New York, NY; Domenic Ciraulo,
`
`The use of NSAIDs did not lead to an increased rate of
`
`
`
`MD, Boston, MA; James Garbutt, MD. Chapel Hill, NC;
`
`
`high values of LCTs for patients taking XR-NTX compared
`
`
`
`Dav