ALKERMES EXHIBIT 2007
`Apotex Inc. v. Alkermes Pharma Ireland Limited
`IPR2025-00514
`
`Page 1 of 8
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`

`

`0145-6008/04/2809-1356$03.00/0
`ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH
`
`Vol. 28, No. 9
`September 2004
`
`A Pilot Evaluation of the Safety and Tolerability of
`Repeat Dose Administration of Long-Acting Injectable
`Naltrexone (Vivitrex®) in Patients With Alcohol
`Dependence
`
`Bankole A. Johnson, Nassima Ait-Daoud, Henri-Jean Aubin, Wim van den Brink, Richard Guzzetta, John Loewy,
`Bernard Silverman, and Elliot Ehrich
`
`Background: Oral naltrexone is currently used as part of a treatment regimen for alcohol-dependent
`patients, but its clinical utility is hampered by poorpatient adherence. A long-acting injectable naltrexone
`formulation (Vivitrex®) was designed to facilitate patient adherence by providing an extended duration of
`therapeutic naltrexone over 1 month, thereby eliminating the need for daily dosing.
`Methods: A multicenter, randomized, double-blind, placebo-controlled pilot study was conducted to
`evaluate the safety and tolerability of intramuscular repeat dose administration of this extended-release
`naltrexone formulation in DSM-IV alcohol-dependentpatients. Thirty patients were randomized totreat-
`ment with injectable naltrexone (400 mg; 1 = 25) or a matching placebo injection (7 = 5) and were dosed
`once every 28 days over 4 months. Psychosocial treatment wasoffered to patients in both treatment groups.
`Outcome measures related to drinking activity and trough plasma concentrations of naltrexone andits
`primary metabolite, 6-8-naltrexol, were evaluated.
`Results: Injectable naltrexone was generally safe and well tolerated. Reported adverse events were mild
`to moderate and resolved without intervention; only two patients discontinued due to adverse events. The
`most common adverse events (nausea and headache) occurred at a similar rate for patients in both
`treatment groups. Pharmacokinetic analysis confirmed that therapeutic levels of naltrexone were delivered
`throughout the four 1-month treatmentcycles.
`Conclusions: Theresults of this pilot study provide the basis and methodsfora larger, more definitive
`trial to determine the utility of this long-acting injectable naltrexone formulation in the treatment of
`alcohol-dependentpatients.
`Key Words: Alcohol, Naltrexone, Treatment, Opioid, Humans.
`
`RADITIONALLY, THE TREATMENT of alcohol
`dependence has been based on various forms of coun-
`seling, including self-help groups, psychosocial approaches,
`and other relapse-prevention techniques. Although psycho-
`and behavioral
`therapies help many alcohol-
`dependent persons to reduce alcohol consumption and
`maintain abstinence, 40-70% of patients who achieve ab-
`stinence from alcohol after detoxification or psychosocial
`
`From the University of Texas Health Science Center at San Antonio, San
`Antonio, Texas (BAJ, NA-D); Alcohol Treatment Center, Emile Roux Hos-
`pital, Limeil-Brévannes, France (H-JA); Amsterdam Institute of Addiction
`Research, Amsterdam, The Netherlands
`(WvdB); Touchstone Medical
`Group, Clovis, California (RG); and Alkermes, Inc., Cambridge, Massachu-
`setts (IL, BS, EE).
`Received for publication March 10, 2004; accepted May 28, 2004.
`Supported by NIAAA Grant N43 AA01002.
`Reprint requests: Bankole A. Johnson, MD, PhD, Department of Psychi-
`atry, The University of Texas Health Science Center at San Antonio, 3939
`Medical Dr., Ste. 100, San Antonio, TX 78229-3900; Fax: 210-562-5403;
`E-mail: bjohnson@uthscsa.edu.
`
`or behavioral treatment resume drinking within 1 year of
`such treatment (Swift, 1999),
`Advances in neuroscience research and in our under-
`standing of the pharmacology of alcohol during the past
`two decades have led to the development of medications to
`improve the efficacy of concurrent pharmacological and
`psychosocial approaches
`to treat alcohol dependence
`(Johnson and Ait-Daoud, 1999). Naltrexone, a p-opioid
`receptor antagonist, was approved for the treatment of
`alcohol dependence in the United States in 1994. Perhaps,
`by modulation of central dopamine function through re-
`duced endogenous opioid receptor activity (Johnson and
`Ait-Daoud, 2000), naltrexone might
`reduce
`alcohol-
`induced reward, including craving (O’Malley et al., 2002).
`In
`two
`pivotal
`randomized,
`double-blind,
`placebo-
`controlled studies of alcohol-dependentpatients, daily nal-
`trexone
`tablets
`combined with psychosocial
`therapy
`reduced 3-month relapse rates from 50% among placebo-
`treated patients to 25% among patients who received nal-
`
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`INJECTABLE NALTREXONE IN ALCOHOL-DEPENDENT PATIENTS
`
`1357
`
`drinking, to decrease the numberof drinks consumed when
`relapse occurs, and to promote abstinence in alcohol-
`dependentpatients (Anton et al., 1999; Kiefer et al., 2003;
`O’Brien et al., 1996; O’Malley et al., 1992; Volpicelli et al.,
`1992; cf Kranzler et al., 2000; Krystal et al., 2001).
`Poor adherence to therapy can limit naltrexone’s effec-
`tiveness and broader clinical utility (Johnson and Ait-
`Daoud, 2000). Indeed, in a 3-month follow-up study, Vol-
`picelli et al. (1997) found that only patients who took their
`oral daily dose of naltrexone on 90% of study days experi-
`enced an improvement
`in drinking outcomes, whereas
`among less compliant patients (who took the dose on less
`than 90% of study days), no significant differences between
`the naltrexone and placebo groups were found for any
`dependent drinking measure, and 50% of them changed
`their drinking behavior from abstinence to clinically signif-
`icant drinking during the study. Similarly, in the large-scale
`UKcollaborative study of Chick et al. (2000), only patients
`who took at least 80% of their naltrexone tablets experi-
`enced better drinking outcomes than those taking placebo
`over 12 months.
`Vivitrex® (naltrexone for injectable suspension; Alkermes,
`Inc., Cambridge, MA), a long-acting formulation of nal-
`trexone, was designed to facilitate adherence to treatment
`by providing therapeutic levels of naltrexone over 1 month
`an
`intramuscular
`(im)
`injection
`of drug-
`encapsulated microspheres, thus eliminating the need for
`daily oral dosing. Monthly extended-release im naltrexone
`administration also might lessen the daily peak-to-trough
`levels that are apparent with oral dosing. Compared with
`oral dosing, the relatively lower naltrexone plasma levels
`from im administration would be expected to result in
`reduced levels of 6-B-naltrexol (naltrexone’s primary me-
`tabolite). Increased 6-f-naltrexol levels have been associ-
`ated with greater frequency and severity of naltrexone-
`associated adverse events (King et al., 1997). Thus, this
`injectable naltrexone formulation might reduce the limita-
`tions of oral naltrexone while retaining the potential to
`effectively treat alcohol dependence.
`The formulation’s extended-release drug delivery tech-
`nology (Medisorb®; Alkermes, Inc., Cambridge, MA) uses
`injectable, biodegradable, polymeric microspheres as the
`delivery medium. The microspheres (approximately 100
`pm in diameter) are composed of naltrexone incorporated
`into a matrix of polylactide-co-glycolide (PLG). PLG is a
`common biodegradable medical polymer with a history of
`safe human use in sutures, bone plates, abdominal mesh,
`and extended-release pharmaceuticals. Once injected into
`the body, the PLG slowly hydrolyzes into lactic and glycolic
`acids, which are naturally occurring metabolic intermedi-
`ates. Lactic and glycolic acids are further metabolized into
`carbon dioxide and water. The ratio of lactide to glycolide
`in the polymer, the polymer molecular weight, and other
`
`released continuously from the
`
`erosion, naltrexone is
`microspheres.
`This pilot study was designed to assess the safety and
`tolerability of repeat-dose im naltrexone over 4 months in
`DSM-IV—diagnosed alcohol-dependent patients. Outcome
`measures related to safety, tolerability, drinking activity,
`and trough plasma concentrations of naltrexone and 6-B-
`naltrexol after repeat dosing were evaluated.
`
`Patient Enrollment and Assessment
`
`METHODS
`
`The study population consisted of men and nonpregnant women 18
`years or older who met DSM-IV criteria for alcohol dependence. We
`included patients who were physically healthy, as evidenced by nonpatho-
`logic biochemical and hematological
`tests, and with hepatic enzymes
`(except y-glutamyl transferase; GGT) no greater than 3 times the upper
`limit of normal. Eligible patients also had to refrain from drinking for at
`least 5 days before study enrollment. We excluded patients with clinically
`significant medical conditions requiring immediate treatment to avoid
`deterioration (including hyperbilirubinemia), as well as otheraxis J diag-
`noses, including narcotic or benzodiazepine dependence (but not nicotine
`dependence). Also excluded were patients treated with naltrexone 10 days
`or less before screening and those intolerant
`to naltrexone; users of
`opiates within 2 weeks of screening; and those receiving pharmacological
`treatment for alcohol dependence (e.g., disulfiram, acamprosate, or on-
`dansetron). Pregnant or breast-feeding women werenot studied. Included
`women of childbearing potential were required to use an acceptable
`method of contraception: hormonal contraception, surgical sterilization,
`or condom plus barrier.
`The study protocol was approved by each study site’s governing insti-
`tutional review board/independent ethics committee. All participants pro-
`vided written, informed consent before enrollment.
`
`Study Design and Procedure
`
`A 4-month double-blind, placebo-controlled, randomized study was
`performed at two sites in the United States and two sites in Europe.
`Eligible patients were randomized in a 5:1 ratio to either injectable im
`naltrexone (400 mg) or im placebo (i.e., a matching volume of micro-
`spheres without naltrexone). Injections were administered im every month
`for 4 months—atotal of four injections. All patients received psychosocial
`support.
`Potential patients who had provided informed consent were screened 7
`days or less before the administration of study drug (day 0). At screening,
`we determined patient eligibility, collected demographic and medical
`information, assessed DSM-IV criteria to diagnose alcoho] dependence,
`measured alcohol dependence severity by using the Alcohol Dependence
`Scale (Skinner and Horn, 1984), recorded baseline alcohol drinking be-
`havior, and performed routine safety and laboratory evaluations.
`Onday 0, enrolled patients were administered the first dose of study
`drug. Subsequent doses were administered on days 28, 56, and 84. The im
`injections (up to 4 ml) were administered as a gluteal injection, and
`injection sites were alternated between the left and right gluteal muscles
`with each subsequent dose. The injections were administered to each
`patient by a nurse or physician. Follow-up visits were scheduled at weeks
`2, 3, 4, 6, 8, and 12 after the initial dose of study medication. Additionally,
`patients were evaluated 30 days and 60 days (+2 days) after the last
`injection or early termination. Blood samples were collected for hematol-
`ogy, chemistry, and urinalysis, and trough plasma naltrexone and 6-B-
`naltrexol concentrations were determined before dosing on days 0, 28, 56,
`and 84. Safety and kinetic assessments were performed at
`the two
`
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`

`Blood samples obtained for drug concentration measurements were
`collected in 10-ml polypropylene EDTA blood tubes, which were centri-
`fuged at 2 to 8°C at 2000 x g for 4 min. At least 4 ml of plasma was
`transferred into two separate tubes, which were frozen at —20°C. After the
`addition of naloxone asthe internal standard, plasma samples were mixed
`with ethyl acetate and hexane underalkaline conditions and then centri-
`fuged. The organic phase was removed and evaporated, and then the
`mobile phase was added to reconstitute the sample. An aliquot of the
`reconstituted extract was then injected onto an Applied Biosystems/MDS
`SCIEX API 3000™ LC-MS-MSSystem (Foster City, CA) equipped with a
`high-performance liquid chromatography column to determine plasma
`concentrations of naltrexone and 6-f-naltrexol.
`Alcohol consumption was measured by using the timeline follow-back
`(TLFB) method (Sobell and Sobell, 1992). Drinking history for the month
`before screening was recorded at
`the screening visit and after each
`month’s medication dose. GGT was used as a biochemical marker of
`heavy drinking (Conigrave et al., 2002; Johnsonet al., 2003).
`Participants received psychosocial support at each monthly study visit.
`For the two European centers, psychosocial support reflected common
`best practice. At a minimum,this included a biopsychosocial evaluation
`and feedback to the patient, education, motivation, strategies for change,
`and monitoring. For two centers in the United States, patients received
`standardized biopsychosocial support with the BRENDA model (Volpi-
`celli et al., 2001). BRENDAis a psychosocial intervention that focuses on
`motivating patients to change and on adhering to treatment (Kaempf et
`al., 1999; Pettinati et al, 2000). The core components of BRENDA
`include biopsychosocial assessment, reporting the assessment to the pa-
`tient, an empathetic approach, identified and stated patient needs, direct
`advice to stop or decrease alcohol consumption and comply with treat-
`ment and assessmentof the patient’s reaction to the advice.
`
`Outcome Measures
`
`Criteria for evaluating safety included the incidence of adverse events,
`injection site assessment findings, laboratory test results (blood chemistry,
`hematology, and urinalysis), and physical examination findings. Pharma-
`cokinetic parameters included repeated predosing plasma naltrexone and
`6-8-naltrexol trough levels.
`Alcohol consumption was recorded and analyzed to assess data collec-
`tion methods. Outcome measures collected by the timeline follow-back
`(TLFB) method included the following:
`
`1. Percentage of heavy drinking days, where heavy drinking was defined as
`five or more drinks per day for men or four or more drinks per day for
`women.
`
`2. Percentage of days abstinent from alcohol.
`3. Number of drinks per drinking day.
`
`Change in GGT levels during the study was used as a biochemical
`marker of heavy alcohol consumption.
`
`Statistical Methods
`
`Because this wasa pilot study,the a priori analyses forthis clinicaltrial
`were descriptive, and summarystatistics were derived forall variables. No
`inferential statistical tests were performed. The purpose of the placebo
`group was to blind both investigators and patients to treatment, thus
`allowing unbiased evaluation of the causality and severity of adverse
`events. All randomized patients who received at least one treatment were
`included in the safety analysis. Activities events were coded and tabulated
`by Medical Dictionary for Regulatory Activities preferred body system
`
`JOHNSONET AL.
`
`RESULTS
`
`Study Population
`Thirty patients were enrolled in this trial and were ran-
`domized according to the planned 5:1 (active:placebo) ra-
`tio; 25 patients were randomized to treatment with inject-
`able naltrexone, and 5 were randomized to placebo
`treatment. Patient demographics and baseline characteris-
`tics are summarized in Table 1. The mean age of the study
`patients was 42.6 years, and 73.3% of patients were men.
`All five patients assigned to the placebo treatment group
`were men, whereasall eight women were in the injectable
`naltrexone treatment group. Apart from gender distribu-
`tion, patient demographics were similar between treatment
`groups.
`Alcohol problem severity was moderate (mean Alcohol
`Dependence Scale score, 17.8) for the cohort but was
`slightly higher among placebo versus injectable naltrexone
`recipients—23.8 vs. 16.6, respectively. The most common
`treatment goal was total abstinence, reported by 17 patients
`(56.7%). Seven patients (23.3%) had a goal of occasional
`use; five patients (16.7%) had a goal of regular but con-
`trolled use, and one patient (3.3%) had a goal of total
`abstinence with a possible relapse. In the month before
`screening, patients consumed an average of 7.9 drinks per
`drinking day, with a mean of 60.8% drinking days and 47.5
`heavy-drinking days (Table 2).
`
`22
`8
`
`(73.3)
`(26.7)
`
`17
`8
`
`(68.0)
`(82.0)
`
`5
`0
`
`(100)
`
`42.6 (9.2)
`26-58
`
`42.1 (9.4)
`26-58
`
`45.2 (8.2)
`32-54
`
`2
`19
`5
`4
`
`(6.7)
`(63.3)
`(16.7)
`(43.3)
`
`2
`15
`4
`4
`
`(8.0)
`(60.0)
`(16.0)
`(16.0)
`
`0
`4
`1
`0
`
`(80.0)
`(20.0)
`
`Table 1. Patient Demographics and Baseline Characteristics
`Treatment group
`Injectable
`naltrexone
`
`Variable
`All subjects
`—(Vivitrex®)
`Placebo
`No. subjects dosed
`30
`25
`5
`Gender, n (%)
`Male
`Female
`Age(years)
`Mean (SD)
`Range
`Race, n (%)
`Black
`Caucasian
`Other
`Not collected
`Weight (kg)
`Mean (SD)
`Range
`ADS score
`Mean (SD)
`Range
`Treatment goal, n (%)
`Total abstinence
`Total abstinence with possible
`relapse
`2
`5
`7
`Occasional use
`0
`0
`0
`Temporary abstinence
`0
`(20.0)
`5
`(16.7)
`5
`Regular but controlled use
`0
`
`82.4 (15.4)
`50-115
`
`83.8 (16.1)
`50-115
`
`75.6 (9.8)
`63-86
`
`17.8 (8.8)
`4-39
`
`16.6 (8.2)
`4-39
`
`23.8 (10.0)
`13-36
`
`17.
`1
`
`(6.7)
`(8.3)
`
`14
`1
`
`(56.0)
`(4.0)
`
`3
`0
`
`(60.0)
`
`(23.3)
`
`(20.0)
`
`(40.0)
`
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`INJECTABLE NALTREXONE IN ALCOHOL-DEPENDENT PATIENTS
`
`1359
`
`
`
`
`
`
`
`
`
`Piacebo
`
`70
`
`Mean%ofHeavy-DrinkingDays
`
`Table 2. Prestudy and On-Study Drinking Behavior
`Treatment group
`Injectable
`naltrexone
`(Vivitrex®)
`Placebo
`
`Variable
`All subjects
`(n = 25)
`(n = 5)
`
`Prestudy?
`Days abstinent (%)
`Drinks per drinking day
`Heavy-drinking days (%)
`Predose GGT(units/liter)
`
`Days on study after
`dosing
`Days abstinent (%)
`Drinks per drinking day
`No. of heavy-drinking
`
`39.2 (33.8)
`7.9 (4.0)
`47.5 (35.0)
`
`39.2 (34.2)
`7.4 (3.9)
`45,3 (35.2)
`81.1 (127.0)
`
`39.3 (35.4)
`10.3 (4.3)
`58.6 (35.8)
`33.8 (19.1)
`
`125.9 (30.1)
`
`120.0 (49.3)
`
`69.4 (33.7)
`3.8 (1.8)
`15.4 (24.9)
`
`62.6 (61.4)
`6.0 (0.8)
`23.4 (44.4)
`
`25.3 (35.0)
`11.7 (17.8)
`Heavy-drinking days (%)
`
`Postdose GGT(units/liter) 30.8 (16.5) 48.5 (62.6)
`
`Values are mean (SD); GGT, y-glutamyltransferase.
`4 Self-reported drinking behavior within 28 days before screening.
`
`Table 3. Patient Disposition
`Treatment group
`Injectable
`naltrexone
`
`Variable
`All subjects
`(Vivitrex®)
`Placebo
`No. randomized
`30
`25
`5
`No. dosed
`30
`25
`5
`Total no. doses
`received, n (%)
`
`2 (7%)
`3 (10%)
`1 (8%)
`24 (80%)
`21 (70%)
`
`2 (7%)
`1 (8%)
`
`1 (4%)
`3 (12%)
`1 (4%)
`20 (80%)
`17 (68%)
`
`2 (8%)
`1 (4%)
`
`1 (20%)
`0
`0
`4 (80%)
`4 (80%)
`
`0
`0
`
`Completed, n (%)
`Discontinued, n (%)
`Adverse event
`Subject
`noncompliance
`Subject withdrew
`2 (7%)
`1 (4%)
`1 (20%)
`consent
`
`Lost to follow-up 0 4 (13%) 4 (16%)
`All percentages are based on the number of subjects dosed.
`
`
`
`
`
`Patient Disposition
`Twenty-four subjects (20 injectable naltrexone-treated
`patients and 4 placebo-treated patients) received all 4 doses
`of study medication; of these, 21 patients (17 injectable
`naltrexone; 4 placebo) successfully completed the study. Of
`the nine patients who discontinued prematurely, eight had
`received injectable naltrexone, and one had received pla-
`cebo. Table 3 summarizes patient disposition and reasons
`for discontinuation by treatment group. All 30 randomized
`patients received at least 1 cycle of treatment.
`
`Evaluation of Outcomes Related to Drinking Behavior
`Double-blind drinking behavior is summarized bytreat-
`ment group in Table 2. Compared with their prestudy
`drinking behavior, patients treated with injectable naltrex-
`
`
`
`
`© Pre-study [ On-study
`
`
`
`
`
`
`
`
`
`
`
`25.3
`
`
`
`injectable naltrexone
`(Vivitrex®)
`
`Fig. 1. Mean percentage of heavy-drinking days, pre-study and during the
`treatment period.
`
`vs. 39.2% before the study) and a reduction in both the
`numberof drinks per drinking day (3.8 vs. 7.4 before the
`study) and the percentage of heavy-drinking days (11.7vs.
`45.3% before the study). Improvements in outcomes re-
`lated to drinking behavior were also demonstrated by pa-
`tients receiving placebo injection plus psychosocial therapy;
`however, changes were not as pronounced. For example,
`the mean percentage of heavy drinking days was reduced to
`25.3% for placebo-treated patients, compared with 11.7%
`for patients receiving injectable naltrexone (Fig. 1).
`Patients treated with injectable naltrexone experienced a
`meanreduction of —32.6 units/liter (SD, 70.1 units/liter) in
`serum GGTactivity from predose levels. Patients treated
`with placebo had a mean reduction of —3.0 units/liter (SD,
`4.0 units/liter).
`
`Clinical Laboratory Evaluation
`No clinically significant changes from baseline levels
`were observed. Analysis of individual hematology and uri-
`nalysis values revealed no significant changes from baseline
`for any parameter for patients in either treatment group.
`Before the second injection, the mean trough plasma
`naltrexone concentration was 1.23 ng/ml (SD, 0.83 ng/ml),
`and this remained relatively constant for the remainder of
`the study; the average mean trough naltrexone level was
`1.33 ng/ml (SD, 1.74 ng/ml). Trough 6-f-naltrexol concen-
`trations were slightly higher than those observed for nal-
`trexone. The mean concentration before the second injec-
`tion was 2.91 ng/ml (SD, 2.17 ng/ml), and this did not
`increase significantly with subsequent doses; the average
`mean trough 6-f-naltrexol concentration was 3.03 ng/ml
`(SD, 3.29 ng/ml).
`
`Safety Evaluation
`
`Page 5 of 8
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`

`

`8 (32)
`4 (16)
`3 (42)
`
`8 (32)
`6 (24)
`4 (16)
`3 (12)
`
`4 (20)
`4 (20)
`0
`
`4 (20)
`0
`1 (20)
`0
`
`Table 4. Most Common Adverse Events by Treatment Group®
`Treatment group
`Injectable
`naltrexone
`System organ class preferred term
`(Vivitrex®)
`Placebo
`
`(MedDRA}
`(n = 25)
`(n = 5)
`No. (%) with AE
`23 (92)
`4 (80)
`Nervous-system disorders
`Headache NOS
`Dizziness
`Somnolence
`Gastrointestinal disorders
`Nausea
`Abdominal pain NOS
`Dry mouth
`Vomiting
`General disorders and administration-site
`conditions
`Injection site pain
`4 (16)
`0
`Fatigue
`3 (12)
`0
`Metabolism and nutrition disorders
`
`Appetite decreased NOS 1 (20) 3 (12)
`MedDRA, Medical Dictionary for Regulatory Activities; AE, adverse event;
`NOS, not otherwise specified.
`2 Occurring in =10% of patients on study.
`
`
`
`placebo group reported at least 1 adverse event during the
`course of the study. The most frequent adverse events
`(occurring in =10% of patients in the study) are shown by
`treatment group and body system in Table 4. Headache and
`nausea were the most common adverse events among pa-
`tients in both treatment groups.
`Data indicate that injectable naltrexone was generally
`well tolerated. No serious adverse events occurred. The
`vast majority of adverse events were judged to be mild or
`moderate in severity. One severe event of hepatomegaly,
`determined to be unrelated to the use of study medication,
`was reported by one patient in the injectable naltrexone
`treatment group.
`Two patients in the injectable naltrexone treatment
`group discontinued participation in the study due to ad-
`verse events (injection site induration and angioedema).
`Both events were moderate in severity and occurred after
`the second dose of injectable naltrexone.
`
`DISCUSSION
`
`Several clinical studies have shown that naltrexone, with
`daily oral administration,
`reduces drinking in alcohol-
`dependentpatients. Nevertheless, a major obstacle to nal-
`trexone’s effectiveness in general clinical practice is that
`tolerance to its adverse events is only moderate. The pri-
`mary objective of this pilot study was to assess the safety
`and tolerability of repeat-dose im administration of an
`extended-release injectable formulation of naltrexone in
`alcohol-dependentpatients. Developed to facilitate adher-
`ence by eliminating the need for daily self-dosing by the
`patient, the extended-release injectable formulation was
`
`JOHNSONET AL.
`
`ing the repetitive peak-to-trough plasma naltrexone levels
`associated with daily oral naltrexone administration.
`The primary finding was that injectable naltrexone was
`generally safe and well tolerated when administered im to
`alcohol-dependent patients once a month during the
`4-month treatment period. No serious adverse events oc-
`curred, and only two patients discontinued the study be-
`cause of adverse events. Similar to the results of a previous
`study of this injectable naltrexone formulation in healthy
`volunteers (Osborn et al., 2000), the incidence of adverse
`events was generally similar to that observed with placebo.
`The most common adverse events (nausea and headache)
`had a similar rate of occurrence for patients in both treat-
`ment groups.
`Pharmacokinetic analyses demonstrated that therapeutic
`levels of naltrexone were delivered by the extended-release
`injectable formulation throughout each 1-month treatment
`cycle. Plasma concentrations of 6-B-naltrexol (naltrexone’s
`major metabolite) were slightly higher than those of plasma
`naltrexone but were substantially lower than those seen
`after oral administration, as reported in previous published
`studies (King et al., 1997).
`Adherence to treatment in this study was generally high,
`and a similar percentage of patients in both treatment
`groups received all four cycles of treatment. In one previ-
`ous clinical trial of patients treated with oral naltrexone,
`more than 40% of patients did not adhere to the daily oral
`regimen; their outcomes were similar to those of placebo-
`treated patients (Chick et al., 2000). Use of extended-
`release injectable naltrexone may, therefore, afford an op-
`portunity to achieve high adherence rates when treating
`alcohol-dependent patients.
`Because this was a pilot study, it was not designed to
`include a formal evaluation of efficacy, nor was it powered
`to demonstrate a treatment effect. Nevertheless, analysis of
`on-study drinking behavior revealed that patients treated
`with injectable naltrexone experienced relative improve-
`ments in the percentage of days abstinent, the number of
`drinks per drinking day, and the number and percentage of
`heavy-drinking days compared with their prestudy drinking
`behavior. The variability of drinking outcomes observed
`was generally comparable to results of previous clinical
`trials, and data indicated that drinking outcomes were in-
`fluenced by key baseline variables before dosing (e.g., dif-
`ferences in outcomes related to drinking behavior may
`reflect differences in baseline drinking behavior between
`treatment groups). Nevertheless, the approximately 50%
`greater reduction in the mean percentage of heavy-drinking
`days for patients in the injectable naltrexone—treated
`group, as reported by the TLFB method,is suggestive of a
`treatment effect.
`In summary, the results of this pilot study evaluating the
`safety and tolerability of repeated administration of the
`long-acting injectable formulation of naltrexone are en-
`
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`INJECTABLE NALTREXONEIN ALCOHOL-DEPENDENT PATIENTS
`
`1361
`
`by this once-a-month injectable formulation. Large-scale
`placebo-controlled treatment studies are now needed to
`determine whetherthis injectable naltrexone formulation is
`more effective than placebo at improving the drinking out-
`comes of alcohol-dependentpatients.
`
`Kranzler HR, Modesto-Lowe V, Van Kirk J (2000) Naltrexone vs. nefa-
`zodone for treatment of alcohol dependence. A placebo-controlled
`trial. Neuropsychopharmacology 22:493-503.
`Krystal JH, Cramer JA, Krol WF, Kirk GF, Rosenheck RA (2001) Nal-
`trexone in the treatment of alcohol dependence, Veterans Affairs Nal-
`trexone Cooperative Study 425 Group. N Engl J Med 345:1734-1739.
`O’Brien CP, Volpicelli LA, Volpicelli JR (1996) Naltrexone in the treat-
`ment of alcoholism: a clinical review. Alcohol 13:35-39,
`
`REFERENCES
`
`Anton RF, Moak DH, Waid LR, Latham PK, Malcolm RJ, Dias JK (1999)
`Naltrexone and cognitive behavioral therapy for the treatment of out-
`patient alcoholics: results of a placebo-controlled trial. Am J Psychiatry
`156:1758-1764.
`
`O’Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville
`B (1992) Naltrexone and copingskills therapy for alcohol dependence:
`a controlled study. Arch Gen Psychiatry 49:881—887.
`O'Malley SS, Krishnan-Sarin S, Farren C, Sinha R, Kreek J (2002) Nal-
`trexone decreases craving and alcohol self-administration in alcohol-
`dependent
`subjects
`and
`activates
`the
`hypothalamo-pituitary-
`Chick J, Anton R, Checinski K, Croop R, Drummond DC, FarmerR,et
`adrenocortical axis, Psychopharmacology 160:19-29.
`al. (2000) A multicentre, randomized, double-blind, placebo-controlled
`Osborn C, Benziger D, Henderson J, Ehrich E, Mant T, Bartus R (2000)
`trial of naltrexone in the treatment of alcohol dependence or abuse.
`Alcohol Alcohol 35:587-593.
`Sustained, 30-day therapeutic levels of naltrexone in a phaseIclinical
`study. Presentation at the American College of Neuropsychopharma-
`Conigrave KM, Degenhardt LJ, Whitfield JB, Saunders JB, Helander A,
`cology 39th Annual Meeting, San Juan, Puerto Rico.
`Tabakoff B (2002) CDT, GGT, and AST as markersof alcohol use: the
`Pettinati HM, Volpicelli JR, Pierce JD Jr, O’Brien CP (2000) Improving
`WHO/ISBRA collaborative project, WHO/ISBRA Study Group. Alco-
`naltrexone response: an intervention for medical practitioners to en-
`hol Clin Exp Res 26:332-339,
`hance medication compliance in alcohol dependent patients. J Addict
`Johnson BA, Ait-Daoud N (1999) Medications to treat alcoholism. Alco-
`Dis 19:71-83.
`hol Res Health 23:99-106.
`
`Johnson BA, Ait-Daoud N (2000) Neuropharmacological treatments for
`alcoholism: scientific basis and clinical findings. Psychopharmacology
`149:327-344,
`Johnson BA, Ait-Daoud N, Bowden CL, DiClemente CC, Roache JD,
`Lawson K, Javors MA, Ma JZ (2003) Oral topiramate for treatment of
`alcohol dependence: a randomised controlled trial. Lancet 361:1677-
`
`Kaempf G, O’Donnell C, Oslin DW (1999) The BRENDA model: a
`psychosocial addiction model to identify and treat alcohol disorders in
`elders. Geriatr Nurs 20:302-304,
`Kiefer F, Jahn H, Tarnaske T, Helwig H, Briken P, Holzbach R,etal.
`(2003) Comparing and combining naltrexone and acamprosate in re-
`lapse prevention of alcoholism: a double-blind, placebo-controlled
`study. Arch Gen Psychiatry 60:92-99.
`King AC, Volpicelli JR, Gunduz M, O’Brien CP, Kreek MJ (1997) Nal-
`trexone biotransformation and incidence of subjective side effects: a
`preliminary study. Alcohol Clin Exp Res 21:906-909.
`
`Skinner HA, Horn JL (1984) Alcohol Dependence Scale: User’s Guide.
`Addiction Research Foundation, Toronto.
`Sobell LC, Sobell MB (1992) Timeline follow-back: a technique for as-
`sessing self-reported alcohol consumption, in Measuring Alcohol Con-
`sumption: Psychosocial and Biochemical Methods (Litten RZ, Allen JP
`eds), pp 41-72. Humana Press, Totowa, NJ.
`Swift RM (1999) Drug therapy for alcohol dependence. N Engl J Med
`340:1482-1490.
`
`Volpicelli JR, Alterman AI, Hayashida M, O’Brien CP (1992) Naltrexone
`in the treatment of alcohol dependence. Arch Gen Psychiatry 49:876—-—
`880.
`
`Volpicelli JR, Pettinati HM, McLellan AT, O’Brien CP (2001) Combining
`Medication and Psychosocial Treatments for Addictions: The BRENDA
`Approach, Guilford Press, New York.
`Volpicelli JR, Rhines KC, Rhines JS, Volpicelli LA, Alterman AI,
`O’Brien CP (1997) Naltrexone and alcohol dependence. Role of subject
`compliance. Arch Gen Psychiatry 54:737-742.
`
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