IV.
`
`RECOMMENDATIONS
`
`A. OPDRA has no objections to the use of the proprietary name, Suboxone.
`
`B. OPDRA recommends the above labeling revisions which might lead to safer use of
`the product.
`
`OPDRA would appreciate feedback of the final outcome of this consult (e.g. copy of the
`revised label/labeling/packaging). We would be willing to meet with the Division for
`further discussion, if needed. If you have further questions or need clarifications, please
`contact Lauren Lee, Pharm.D. at (301)827-3243.
`
`-lSI
`
`J
`
`Lauren Lee, Phann.D.
`Safety Evaluator
`Office of Post-Marketing Drug Risk Assessment
`
`loncur: lSI
`
`y-_] ,, ) \\ ~ 1
`-=------,-y--
`Jerry Philtlps, RPh
`Associate Director for Medication Error Prevention
`Office of Post-Marketing Drug Risk Assessment
`
`-
`
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`ON ORIGINAL
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`ABUSE LIABILITY REVIEW
`
`NDA#:
`
`20-733
`
`TRADE NAME:
`
`SUBOXONE®
`
`DRUG:
`
`Buprenorphine Hydrochloride /Naloxone
`Hydrochloride Sublingual Tablets
`
`SPONSOR: Reckitt & Colman Pharmaceuticals, Inc.
`(Fhe National Institute on Drug abuse (N/DA) and Reckitt & Colman
`have entered a Cooperative Research & Development Agreement
`(CRADA) to develop the product for the indication. Through NIDA(cid:173)
`funded studies, buprenorphine has been studied for the indication under
`47 different INDs)
`
`PROPOSED INDICATION: Treatment of Opiate Dependence
`
`'
`DOSAGE FORMS: Sublingual tablets of2 mg buprenorphine + 0.5 mg naloxone
`and 8 mg buprenorphine + 2.0 mg naloxone
`
`DATE OF NDA SUBMISSION:
`
`June 7, 1999
`
`DATE OF REVIEW:
`
`October 7, 1999
`
`REVIEWER:
`
`Michael Klein, Ph.D. [
`
`}
`
`The Sponsor submitted for Agency review the following data and information in NDA #
`20-733, as the abuse liability section of the NDA:
`
`1. Summary and description of drug abuse and dependence st\:,dies on buprenorphine
`dosage forms.
`
`This includes some preclinical studies described in the original buprenorphine
`product (Buprenex; NDA # 18-401) which are applicable to the abuse liability
`assessment of the NDA # 20-733 and # 20-732.
`
`2. Actual experience reports of abuse of sublingual preparations ofbuprenorphine
`marketed worldwide:
`
`a France
`b. New Zealand
`c. United Kingdom
`d. Ireland
`
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`2
`
`e. Scotland
`f. Spain
`g. India
`h. Australia
`1. Others (Belgium, Sri Lanka, Germany)
`
`3. Description of issues related to abuse in NDA clinical, pharmacokinetics and
`chemistry sections.
`
`4. Recommendation in the form of an eight factor analysis to place the combination
`product and the single entity buprenorphine (Subutex®) produc; (NDA # 20-732) into
`Schedule V. Although buprenorphine was recommended for Schedule m in the
`pharmacology/toxicology review (March 12, 1981), final placement ofthe product and
`substance was in Schedule V (1985).
`
`In addition, subsequent to filing the original submission, the National Institute on Drug
`Abuse {Nlli/NIDAIMDD) provided additional data:
`
`I. Information on overdoses ofbuprenorphine reported in Frar..ce.
`
`2. Results of a Nlll-funded study (U.S. Public Health Service Research Scientist Award
`K05 DA00050, Scientist Development Award K02 DA 00332, and ROI DA08045
`from the National Institute on Drug Abuse) entitled "Effects ofbuprenorphine versus
`buprenorphinelnaloxone tablets in non-dependent opioid abusers" that has been sent
`to the journal Psychopharmacology for publication.
`
`BACKGROUND:
`
`Jasinski eta/. (1978) were the first to look at the pharmacology and abuse potential of
`buprenorphine. Incarcerated male volunteers with histories of narcotic addiction were
`given single or repeated doses ofbuprenorphine. The single dose study showed
`buprenorphine to have typical morphine-like effects. However, unlike morphine which
`produces effects for approximately 4 to 5 hours, buprenorphine was found to produce
`effects through a 72-hour observation period following administration. Initially in the
`repeated dose study, 5 subjects were administered daily doses ofbuprenorphine. Three
`of the 5 subjects completed the experiment and received buprenorphine for 57
`consecutive days. After the 57th day, buprenorphine was abruptly discontinued~ Several
`days after the cessation ofbuprenorphine was abruptly discontinued. Several days after
`the cessation ofbuprenorphine, subjects began experiencing se11ere withdrawal symptoms
`which were alleviated by gradual, decreasing doses of morphin~ and diazepam.
`
`Jasinski eta/. felt that any substance that has the ability to produce subjective morphine(cid:173)
`like feelings of euphoria, and which can lead to physical dependence has the potential for
`abuse. Buprenorphine was shown to have both of these properties. However, because of
`its long-lasting effects and the low dos~ needed to induce mor.?hine-Iike euphoria, the
`
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`potential for abuse was judged to be less than that of heroin and addicts might be
`successfully maintained on doses administered less frequently than once daily.
`However, with increasing numbers of reports of abuse ofbuprenorphine, that conclusion
`has been increasingly questioned. (Jasinski D. R., Pevnick J. S., Griffith J. D. Human
`pharmacology and abuse potential of the analgesic buprenorphine. Arch. Gen. Psych.,
`35:501-516, 1978).
`
`ABUSE POTENTIAL STUDY OF SUBLINGUAL BUPRENORPBINE
`PRODUCTS
`
`Study: Effects ofBuprenorphine Versus buprenorphine/Naloxone Tablets in Non(cid:173)
`dependent Opioid Abusers
`
`Investigators:
`- .
`-
`-
`--,
`
`Rationale: The characteristics and abuse potential of intact buprenorphine and
`buprenorphine/ naloxone tablets in non-dependent opioid abusers has not been
`determined. Non-parenteral abuse of opioids such as buprenorphine may be more likely
`in people who have less severe substance abuse disorders (that is, are not physically
`dependent upon opioids). While non-dependent opioid abusers may dissolve and inject
`tablets, such populations with less ~vere levels of opioid abuse will have lower rates of
`injecting drug use. These non-dependent abusers may experiment and abuse
`buprenorphine tablets via the sublingual route, if sufficient opioid agonist effects are
`produced. The purpose of this study was to examine the pharmacologic characteristics
`of sublingual buprenorphine/ naloxone tablets in non-dependent abusers, determining if
`buprenorphine effects are modulated by the addition of naloxon.e, and a$SCSSing the
`relative abuse potential of sublingual buprenorphine/naloxone tablets in this population.
`
`Objectives: To assess the abuse potential of sublingual buprenorphine and
`buprenorphine/ naloxone tablets in non-dependent opioid abusers.
`
`Subjects: 7 Adult volunteers with active opioid abuse, but not physically dependent (6
`males/1 female); average age 38.4 years (range 33-47 years). The number of illicit
`opioid uses per week was between 1 and 4.
`
`Study Setting: In-patient. Urine samples collected at admission and intermittently
`throughout participation and tested for the presence of illicit drugs using an EMIT
`system.
`
`Study Procedure: Participants were monitored drug-free for a. minimum of 48 hours
`after admission to study site to ensure they had no evidence of :physical dependence on
`opioids. Each subject participated in a minimum of 13 experimental sessions and resided
`on the ward for 7 weeks.
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`Laboratory Sessions: Subjects were informed they may receiYe combinations of
`buprenorphine and naloxone, and other opioid agonist medications or placebo. Subject
`and observer questionnaires were presented and responses entered. Examples of opioid
`agonists and antagonists and the types of effects produced by each were described to
`participants. Sessions lasted 3 ~ hours. 15 minutes after the start of each session, 15
`minutes of baseline physiological data were obtained, all subject and observer
`questionnaires were completed.
`30 Minutes after the start of the session, participants
`received an intramuscular injection followed by the administration of sublingual tablets.
`The session then continued for 3 hours, with collection of data.
`
`Drugs & Doses: Sublingual buprenorphine ( 4, 8, 16 mg) sub:ingual
`buprenorphinelnaloxone (1/.25, 2/.5, 4/1. 8/2. 16/4 mg), as well as intramuscular
`hydromorphone (2, 4 mg) [serving as positive opiate agonist control] and placebo in
`laboratory sessions conducted twice per week. All medications were administered using
`double-blind and double-dummy procedures.
`
`Measures:
`1. Physiological measures: heart rate, blood pressure, skin temperature, respiratory rate,
`pupil diameter, and oxygen saturation.
`2. · Subject and Observer measures: Subjective effect reports and observer rating
`questionnaires were completed 15 minutes before and at 15 minute intervals up to
`180 minutes following drug administration. Subjects comt:leted visual analog scales
`(High, Drug Effects, Good Effects, Bad Effects, Liking, and Sick), a pharmacological
`class questionnaire, and an adjective rating questionnaire. Each scale was a
`horizontal line on the computer screen, and the subject positioned an intersecting
`vertical line along the horizontal line. Ends of the horizont2!lline were labelled
`''None" and "Extremely" and responses were scored proportionately on a 1 00-point
`·scale. The pharmacological class questionnaire asked the subject to select one of I 0
`drug classes to which the administered drug was most similar. The adjective rating
`questionnaire consisted of37 items which the participant rated on a 5-point setae
`from 0 (not at all) to 4 (extremely); the items constituted 2 scales: a 16-item opioid
`agonist scale (morphine-like effects), and a 21-item Withdrawal scale (adjectives
`associated with opioid withdrawal-like effects). Ratings for individual item were
`summed for a total score for each scale. Observer ratings included the same adjective
`rating scale, as well as an assessment of 7 signs of opioid withdrawal (lacrimation,
`rhinorrhea, perspiration, piloerection, bowel sounds, yawing and restlessness). Each
`opioid withdrawal item was scored either 0, 1, or 2 (with higher scores corresponding
`to greater severity), and scores for all items were summed to prodcue a total observer
`Withdrawal Signs Score. These ratings were done at the same times as the subject
`ratings. Item ratings were summed to produce total scores for the Agonist and
`Withdrawal scale.
`3. Psychomotor/Cognitive Performance measures: 3 Tasks were completed during the
`session: a computerized form of the Digit Symbol Substitution Task, a Circular
`Lights Task, and a computerized form of the Trail-Making Test. Results were
`summarized for sequence errors and length of work product. Each of the 3 tasks were
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`completed during the baseline period (15 minutes before drug administration and at
`the same times as the subject ratings.
`
`Data Analysis: Peak values for each session were determined for each measure. Since
`some measures decrease in response to acute opioid agonist effects, absolute nadir effect
`for these measures was examined.Tukey's honestly significant difference (HSD) was
`used to compare peak saline values to the peak value of each active drug condition. The
`mean square error term needed to perform these tests was calculated using a repeated
`measures, 2-factor analysis ofvariance; main effects were the II drug conditions and
`time (baseline vs. peak effect). Time course effects were analyzed with a repeated
`measures analysis of variance. Main effects were the II drug conditions and 13 time
`points.
`
`Results: Higher doses ofbuprenorphine and buprenorphinelnaloxone produced similar
`opioid agonist-like effects. There was no evidence to suggest that the addition of
`naloxone attenuated opiate agonist effects ofbuprenorphine in this population when
`buprenorphine was delivered by the sublingual route. All drugs produced significant
`effects relative to placebo. There were dose-related increases in ratings of Drug Effects,
`High, Good Effects, and Liking for hydromorphone, buprenorphine and
`buprenorphinelnaloxone. Predominant effects were seen with the highest doses tested.
`There were no increases in ratings ofBad Effects or Sick. The lowest doses tested
`produced ratings that were of modest magnitude, for hydromorphone as well as the
`buprenorphines. Results from the subject adjective rating questionnaire showed only
`the highest doses ofbuprenorphine and buprenorphinelnaloxone producing significantly
`increased ratings relative to placebo. There were no significant results for the subject(cid:173)
`rated adjective score for opioid withdrawal. (See TABLE I below).
`
`Skin temperature was increased for all hydromorphone doses, all buprenorphine doses
`and the highest dose of the combination product. Pupil diameter showed significant
`constriction for all of the doses tested except the lowest dose of the combination product.
`Oxygen saturation was decreased for the 8 and I6 mg buprenorphine doses and the I6/4
`mg buprenorphine naloxone dose.
`
`Results from the psychomotor tasks showed significantly higher changes for the highest
`doses ofbuprenorphine and buprenorphinelnaloxone.
`
`Results from time course effects showed that none of the variables effected
`buprenorphinelnaloxone significantly different from buprenorphine alone, although
`pairwise comparisons against placebo showed that each alone had similar patterns of
`differing from placebo. Neither sublingual buprenorphine nor buprenorphinelnaloxone
`showed onset of effects until 30 minutes after the start of the session. Peak effects did
`not differ from each other or hydromorphone for VAS ratings. The hydromorphone time
`to peak response for physiological measures was significantly s~1orter, however.
`
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`
`TABLE I. Summary of Peak Drug Effects•
`
`6
`
`Measure
`
`Placebo Hydromor-
`pbonei.m.
`2
`4
`
`High
`
`Drug effects
`
`Good effects
`
`Liking
`
`1.6
`
`2.4
`
`2.6
`
`1.3
`
`10.1
`
`23.1•
`
`9.4
`
`9.6
`
`23.3
`
`22.6
`
`11.0
`
`27.3
`
`11.9
`
`11.3
`
`13.7
`
`Buprencxphine
`sublingual
`I s
`I 16
`1125
`4
`Subjective measures (VAS)
`6.9
`22.0*
`29.4
`••
`31.7
`••
`33.4
`••
`32.0
`••
`16.0
`••
`
`BupreoorphineiNaloxone sublingual
`
`I 21.5
`
`9.3
`
`9.S
`
`8.4
`
`104
`
`114
`
`4/1
`
`16.0
`
`17.1
`
`17.6
`
`20.7
`
`12.1
`
`1812
`
`I 16/4
`
`13.6
`
`16.1
`
`16.1
`
`18.6
`
`13.7
`
`26.7••
`
`2S.O
`
`28.3
`
`28.9*
`
`IS.6•
`
`12.0
`
`14.1
`
`9.0
`
`12.0
`
`10.4
`
`11.9
`
`26.6•
`
`IS.1
`
`29.1•
`
`11.4
`
`29.3*
`
`12.0
`
`13.3
`
`11.7
`
`13.1
`
`16.3*
`
`12.9
`
`Observer-rated measures
`16.7
`14.0
`IS.4
`••
`
`124
`
`14.3
`
`19.7 ..
`
`17.9**
`
`Adjective
`agonist
`rating.scale
`
`Adjective
`agonist
`ratina scale
`
`Skin
`tem
`Pupil
`diameter
`Oxygen
`saturation
`
`Circular
`lights
`Trails (total
`line length •
`em)
`
`81.4
`
`4.3
`
`91.0
`••
`3.o••
`
`89.7*
`
`90.0•
`
`2.s••
`
`2.9•
`
`97.9
`
`97.6
`
`97.3
`
`91.S
`
`76.1
`
`71.0
`
`64.0
`
`70.6
`
`S42.0
`
`601.1
`
`609.8
`
`S98.4
`
`96.7
`••
`Psychomotor taSks
`66.0
`60.6
`••
`677.9
`
`68S.S
`
`Phvsiolo~ · c measures
`84.9
`91.8
`91.8
`••
`••
`2.6
`2.4* 0
`••
`97.1
`
`3.7
`
`97.4
`
`870
`
`88.7
`
`88.S
`
`91.4••
`
`3A·••
`
`3.1••
`
`2.6••
`
`2.4••
`
`977
`
`97.7
`
`97.4
`
`97.o••
`
`70.7
`
`71.9
`
`67.0
`
`S4.1**
`
`60.6••
`
`S96.3
`
`SSi.6
`
`S81.3
`
`66S.1
`
`836.4••
`
`avatues shown are the mean peak response (N=7). All doses are in milligrams. Results shown are for
`items with a significant effect for at least one dose condition; comparisons are to peak placebo effect. For
`subjective measures. observer-rated measures, skin temperature. and the Tra.ils outcome the maximum
`positive inaease was examined. For all other physiological measures and Circular lights the maximum
`decrease was examined. *p<O.OS, **p<O.Ol.
`
`Participants' responses to the drug class identification questionnaire are presented in
`TABLE 2 below. Placebo was identified as placebo 7<JO/o of the time. The largest
`number of opiate agonist identifications was for the higher doses ofhydromorphone,
`buprenorphine and buprenorphine/naloxone, although the latter drug group was identified
`as other drug classes between 2% and 19% of the time.
`
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`TABLE 2. DRUG IDENTIFICATION RESPONSES•
`
`7
`
`• Numbers shown are total number of drug identifications made for each dcse
`condition administered. Total identifications for each dose condition = 84
`(7 subjects x 12 times each).
`b A total of34 identifications for Other Oasses (<4%), which are combined numbers
`of identified as Others (28), Opioid Antagonists (2), Benzodiazepioes (2), and
`Stimulants (2). There were no identifications as Antidepressants. Hallucinoges,
`Pheoothiazines, and Barbiturates.
`
`Condusions: This study tested the effects ofbuprenorphine and buprenorphine/
`naloxone only by the sublingual route and in non-dependent volunteers. Results suggest
`sublingual buprenorphine and buprenorphine/ naloxone both may be abused by opioid
`users who are not physically dependent upon opioids, and therefore may be a recreational
`drug of abuse. The authors concluded that buprenorphine and buprenorphine/naloxone
`tablets in the dose range tested have moderate potential for abuse comparable in
`magnitude to 4 mg of parenteral hydromorphone. This study did not test the relative
`abuse potential of parenteral or intranasal administration of the substances, but of the.
`intact dosage form.
`
`The purpose of adding naloxone to buprenorphine is to decrease abuse potential in opioid
`dependent individuals who might inject buprenorphine. In abusers who are not
`physically dependent on opioids, addition of naloxone will not exert a similar precipitated
`withdrawal. There were only small non-significant differences observed between
`buprenorphine and buprenorphinelnaloxone.
`
`REPORTS OF ABUSE OF BUPRENORPHINE SUBLINGUAL TABLETS IN
`NDA #20-733 AND FROM NIDA.
`
`I. Experience in France.
`
`Through the National Institute on Drug Abuse (NIDAIMDD), the following
`_.-
`,France, personal communication,
`communication was received from
`1999, unpublished): "The impact on mortality of buprenorphine availability to drug
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`using subjects in comparison to methadone . .
`_
`. Workinprogress. 1999.
`
`subjects have been
`Over a three-year period (1996-98), during which a little over-
`receiving buprenorphine at any given time, 20 so called "bupre11orphine-related deaths"
`have been reported and documented. Of these, only one had no associated substances
`(benzodiazepines and/or alcohol). All occurred among out-of-treatment subjects (black
`market buprenorphine). During the same time period, for 5,000 methadone subjects, 20
`so called 'methadone-related deaths' have been reported. During the same time period,
`overdose deaths registered by the Police, have gone from over 500/y to 200/y. The
`decrease is due to a decrease of heroin related deaths, medication related deaths are
`unchanged. Of course, there are many approximations in these numbers and caution is
`warranted, but, if anything, what is going on in France seems to support highly the safety
`ofbuprenorphine considering the overall lack of control and the importance of black
`market access and intravenous diversion."
`
`Most of the adverse events reported by subjects receiving buprenorphine in clinical trials
`and by patients receiving Subutex for treatment of opiate addiction in France appear to be
`that of opiate withdrawal. Most commonly reported withdrawal-related symptoms
`include asthenia, hypertonia, headache, lacrimation disorder, nausea, abdominal pain,
`bone pain and rhinitis.
`
`Post-marketing data from France indicate the use ofbuprenorphine (Subutex) among
`pregnant opiate-dependent women that has resulted in a number of neonates experiencing
`some degree of withdrawal symptoms. The level of withdrawal is generally reported to
`be of a low level and short duration. Small open studies ofbuprenorphine in 29 pregnant
`opioid dependent women have shown normal deliveries and only mild neonatal
`withdrawal. Seven fetal deaths among mothers receiving Subu'lex were reported in the
`French post-marketing experience. These fetal deaths occurred among a population at
`extremely high risk for adverse fatal outcomes and there is no dear association between
`the drug and fetal demise for any of these cases. The following publications were
`provided by the author for review.
`
`1. Auriacombe M. Buprenorphine use in France: background and current use. In: Ritter
`A, Kutin J, Lintzeris N, Bammer G ed. Expanding treatment options for heroin
`dependence in Victoria: buprenorphine, LAAM, naltrexone and slow-release oral
`morphine. New pharmacotherapies project - feasibility phase. Fitzroy, Victoria:
`Turning Point Alcohol and Drug Center Inc.; 1997:73-80.
`
`In February 1996, buprenorphine in 0.4, 2 and 8 mg sublingual tablets was made
`officially available for treatment of opiate dependent subjects. In 15 months, it
`was estimated that as many as 40,000 patients were receiving buprenorphine
`prescriptions for treatment of opiate addiction (approximately 25% of total addict
`population). Average prescribed dose is 8 mg daily. Supervision of drug delivery
`to the addicts is conducted by pharmacists. In a survey of2,646 pharmacies, it
`was estimated that 800/o of the Subutex was used in the prescribed way and that
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`700/o of prescriptions were not resold. From these data intravenous injection of
`Subutex was estimated at minimum between 10 to 15% of subjects. Patient
`compliance was considered good in 71% of cases (up to 74% in October 1996).
`As of June 1997, there were some reports of adverse effects with buprenorphine
`use by addicts. One report of6 deaths involved combined use ofbuprenorphine
`i. v. with benzodiazepines and alcohol. All 6 subjects used illegally obtained
`buprenorphine and were not included in a comprehensive treatment program. The
`author points out on balance there was a 200/o reduction in opiate overdose deaths
`during this time (that is, 100 fewer deaths from the usual450-500 annual deaths).
`Another series of adverse effects concerns reports of increases in liver enzymes
`among addicts treated with buprenorphine, leading to the recommendation that
`addict patients on buprenorpbine be closely monitored , as over 75% of opiate
`drug users in treatment in France are positive for hepatitis C virus.
`
`Auriacombe M, Franques P, Bertoprelle V., Tignol J. Use ofbuprenorphine for
`2
`substitution treatment: a French experience in Bordeaux and Bayonne. Research and
`Clinical Forums 1997; 19: 47-50.
`
`The article largely advocates the use ofbuprenorphine in treatment of opiate
`addiction and discusses the successes which include reduction in alcohol and drug
`use after 12 months and improvement in quality of life. The author discusses
`some reports where buprenorphine use was not successful and attributes these to
`insufficient dosing or inadequate counseling programs. This raises the issue of
`determining whether tolerance develops to use ofbuprenorphine and how dosing
`adjustments that may be needed are handled to maintain effectiveness of the drug.
`
`3. Auriacombe M. Overview on substitution treatment for heroin users in France. In:
`Farrell M, Howes S, Verster A, Davoli M ed. Reviewing curre:nt practice in drug
`substitution treatment in Europe (CT. 98 DR.IO). Lisbon: EMCDDA; 1999:61-68.
`
`This article contained the same material as in the 2 previous articles.
`
`Other articles submitted in the NDA:
`
`Arditti, J., Bourdon, J.H., Jean, P., Landi, H., Nasset, D., Jouglard, J., Thirion, X,
`"Buprenorphine abuse in a group of 50 drug-use abusers admitted to MarseiUes
`HospitaL
`
`Buprenorphine was placed on the market in 1987. Its indication is for the rapid treatment
`of intense pain, particularly in postoperative situations. However, abuse of its therapeutic
`use as outlined in the Marketing Authorization was quickly SUSI:>eeted. Buprenorphine is
`prescribed to addicts by certain doctors for opiate withdrawal but is also used illicitly,
`and although its physical dependence potential is less than other morphine products, it
`does give rise to addiction and drug dependence. Through the toxicology activities at
`Marseilles Hospital, urine samples of addicted patients are pro~ided as part of the
`analytic activity at the Drug Dependence Evaluation and Information center: Samples of
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`urines of 50 addicted patients upon admittance to the hospital between June and October
`1992 were sent to the laboratory. Search for the main substances used in drug
`dependence (amphetamines, benzodiazepines, cannabis, cocain1e, opiates) was carried
`out. Buprenorphine and norbuprenorphine were not detected during the search for
`opiates due to the presence of a modified morphinane nucleus and the absence of
`morphine-like metabolism. Although a small sample, the frequency of occurrence of
`each substance was calculated (C.I. at 95% of the percentage). The 50 patients included
`39 males and 11 females. Average age was 28.6 ±5.6 years. A urine sample was
`analyzed for each of these individuals. See TABLE 3.
`
`TABLE 3.
`
`SUBSTANCES IDENTIFIED AMONG THE 50 DRUG ADDICTS.
`
`SUBSTANCE
`
`Heroin
`Benzodiazepines
`Cannabis
`Buprenorphine
`Cocaine
`Amphetamines
`
`Positive samples
`No.
`%
`80
`40/50
`36/50
`72
`10/50
`20
`18
`9/50
`3/50
`6
`0/50
`0
`
`Coof. InteJVal
`(95%of%)
`69 to 91
`61 to 83
`9 to 31
`8to28
`Oto 12
`
`Nine ofthe 50 samples analyzed are positive for buprenorphine and/or norbuprenorphine
`(18%), with a C. I. of between 8 and 28%. The sampled group includes essentially the use
`ofbuprenorphine within the context of heroin addiction (8 cases). In only one case,
`buprenorphine was substituted for heroin in the course of therapeutic withdrawal. These
`9 patients were monitored within the framework of an addiction consultation (3 cases), or
`admission to hospital (6 cases). In September 1992, the Health Minister published
`special conditions for issuing and rpescribing buprenorphine orally for patients not
`admitted to hospital. Prescriptions must be made on a voucher taken from the counterfoil
`book and retained by the pharmacist for a period of3 years.
`
`&ulmevieille M., Horamburu, F., Begaud, B., "Abuse of prescription medicines in
`southwestern France, Ann. Phormocother., 31: 847-850, 1997.
`
`In France, prescription drugs with addiction potential are subject to the recommendations
`of the U.N. and the WHO. Duration of treatment and renewal of prescription medicines
`are strictly limited. Addicts are thus frequently forced to attempt to procure these drugs
`by falsifying a prescription. Theft of prescription forms and blrnk forms and falsification
`original forms are methods that are used. Pharmacies are thus in the front line for
`detection and quantification of this phenomenon. To estimate its magnitude, a survey of
`falsified prescription forms was conducted within a network of pharmacies. A secondary
`objective was that alerting pharmacists to the amount of abuse of prescription medicines
`would help to decrease the problem through more careful screening of prescriptions.
`Falsified prescriptions were used as an indicator of abuse. Community pharmacists in a
`representative network were asked to report any falsified prescription form presented
`over a 1-year period. Sales data were used to express results as abuse rate and abuse rate
`ratio. Two-thirds of the 130 pharmacies in the network reported at least I falsified
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`prescription. The reported incidence of falsified prescriptions was 2.3 per 10,000
`inhabitants. A total of392 falsified prescription forms was collected. The abuse rate
`ratios were 171 (95% CI 140 to 21 0) for dextroamphetmaine-phenobarbital in
`combination, 168 (95% CI 131 to 216) for fenozolone, 67 (95% CI 53 to 84) for
`buprenorphine and 40.5 (95% CI 33 to 50) for clobenzorex.
`
`Falsified or forged medical prescriptions as an indicator of pharmacodependence: A
`pilot study. M Lapeyre-Mestre, C Damase-Michel, P,· Adarm, P. Michaud, J. L
`Montastruc, Eur J Qin Pharmacol (1997) 51:37-39.
`
`Survey of prescription forgeries in community pharmacies in the Midi-Pyrenees area
`(southwest France). Main criteria used to identify forgeries were inadequate dosage,
`multiple use of the prescription form, drafting not in accordance with the rules of
`prescription or false prescription forms (stolen prescription forms, photocopies).
`Results: A total of 165 falsified prescriptions were collected. The 305 drugs involved in
`these forged prescriptions were opiate analgesics, benzodiazepines, amphetamines and
`minor opiate analgesics. Medications were essentially buprencrphine, flunitrazepam
`(2mg dosage), phenobarbitone+amphetamine, and clorazepate. See TABLE 4.
`
`TABLE 4. Top 10 drugs reported in the 165 forged prescription forms
`
`Drugs
`Bupreoorphine
`Fluni
`Ampbetamine+Phenobarbitone
`Clo
`Acetaminophen
`Bro
`Amfeprnmone
`Fenozolone
`Lorazepam
`Clobenzorex
`
`No.
`62
`28
`21
`17
`13
`7
`6
`5
`4
`4
`
`%
`37.6
`17.()
`12.7
`10.3
`7.9
`4.2
`3.6
`3.0
`2.4
`2.4
`
`The most frequently requested drugs, buprenorphine and flunitrazepam, could be used as
`substitute drugs when local availability of heroin decreased. Subjects who presented
`forged prescriptions ofbuprenorphine primarily (85%) men younger than 30 years. The
`pattern ofuse ofbuprenorphine declined from September 1991 to April1993, because of
`a 1992law regulating prescription ofbuprenorphine.
`
`2. Experience in New Zealand.
`
`Dore, G. M., Hargreaves, G., Niven, B. E., Cape, G. S., "Dependent opioid users
`assessed for metluulone treatment in Otago: patterns of drug use," New Zealand Med.
`J., 161-165, 1997.
`
`A retrospective case note review was carried out for 126 consecutive clients who were
`assessed for methadone treatment in the Otago province over a 2-year period. Patterns of
`drug use were assessed. Over 600/o of those presenting were using 3 or more opioid
`
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`drugs, with most common being what is referred to as "homebake" (63%) which is
`largely comprised of the extractives from codeine-containing combination products, as
`well as sustained release morphine sulfate tablets (62%), buprenorphine (52%), opium
`poppies (500/o) and methadone (41%). As access to heroin in the 1990's has been limited,
`heroin use was reported primarily from individuals returning from overseas travel.. The
`majority of injected drugs are pharmaceuticals, "homebake" and opium poppies. Most
`injecting drug users attending methadone clinics in the early 190's were dependent on
`buprenorphine, morphine, opium poppy, extract, methadone, "homebake", meperidine.
`Codeine based tablets and cough syrups were also abused. See TABLE 5.
`
`TABLE 5. Percentage oflndividuals Reporting
`Use of Different Opioids during Prior 3 Months Period.
`
`OPIOIDNAME
`Homebake
`Morphine (sustained release tablets)
`Buprenorphine
`Opium poppies
`Methadone
`Opium tincture
`Codeine
`Meperidine
`DextropropoXYPhene
`Dextromoramide
`Heroin
`Diphenoxylate HCI/atropine sulfate
`Pentazocine
`
`PERCENT
`63
`62
`52
`50
`41
`21
`16
`14
`13
`9
`5
`3
`2
`
`G. M. Robinson, P. D. Dukes, B. J. Robinson, R r. Cooke, and G. N. Mahoney, "The
`misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington,
`New Zealand," Drug and Alcohol Dependence, 33: 81-86, 1993.
`
`Two surveys of 12 months duration were undertaken on opioid users at the Wellington
`Alcohol and Drug Centre before and after introduction of a combination buprenorphine
`0.2 mg- naloxone 0.17 mg tablet (Bu-Nx), which was launched in 1991 in the hope of
`reducing intravenous misuse. There was considerable iv misuse ofbuprenorphine 0.2 mg
`tablets (Bu) in 1990 with self-reports of misuse in 81% ofthe patients over the 4 weeks
`prior to presentation, and 65% of the patients had buprenorphine in their urine. In the
`repeat survey 57% reported misuse of the Bu-Nx combination over the previous 4 weeks,
`and 43% had buprenorphine and naloxone detected in their urine. There was a reduction
`in the street price ofBu-Nx. One third of the patients who used Bu-Nx i.v. reported
`instances of withdrawal symptoms, and subjectively the drug was less attractive to
`misusers, though it remains a drug of abuse. See TABLE 6.
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`TABLE 6. Opioid preparations: Wellington self-reports of any use in previous 4 weeks.
`
`DRUG
`
`Buprenorphine (only)
`Buprenorphine-naloxone (only)
`Buprenorphine & Buprenorphine-naloxone
`Pbannaceutical morphine from long-acting tablets
`'Homebake' (morphine/heroin) made from codeine
`H