eeeenneeenereeeeaeeenSee
`
`
`
`
`
`e
`
`maeaHli
`nec‘aaiome
`
`cal
`
`
`
`
` Larreaareas 7|7|
`
`
`
`
`|
`
`iLeenareemote)
`
`
`
`Ind
`
`ivior
`
`Ex. 1005
`
`Indivior Ex. 1005
`
`

`

`INSTANT ACCESS TO SIX DECADES OF TRUST...
`
`DATE DUE
`
`EBRARY
`
`USETTS
`
`With alliy not use the one from
`E C 3 2003
`obile,PDR* is PDR's FREE'
`the company s.
`hainuiciu
`avaiiaoie Tor ramr us anti rocket PC devices.
`
`RECEIVED
`
`Download mobs/ePDR® at www.PDR.net today for FREE* access to reliable drug information for your handhel
`
`• Rx and OTC drug look-up by brand or
`generic name, therapeutic class or indication
`• Drug interaction check between 2 and 32 drugs
`• Critical drug updates and information in our
`"What's New feature
`• Updated nightly to include any changes to drug information
`• Uses only about 3MB memory on device
`mobiiePDR®
`
`• FREE — entire program and technical support
`have no hidden costs
`• Downloads quickly and easily at www.PDR.net
`• Downloads without interference from your existing desktor
`or ISP firewall
`• Allows you to update content and software whenever you
`sync — no more installing and uninstalling to get new featin
`
`. Consider the source.
`
`"THOM* SC)I\1
`
`PDR
`
`For nearly 60 years, doctors have relied upon the PDR® for the latest drug information. Today, consumers too can source reliable informal
`about detecting, preventing and treating a variety of medical conditions at www.PDRhealth.com. PDRhealth.com is a website that provic
`you with concise and accurate healthcare and drug information from a trusted source; the publishers of the PDR®.
`
`•The download of mobilePDR is free to U.S.-based MDs, DOs, NPs, and PAs in full-time patient practice, and to U.S. medical students and residents.
`
`

`

`PDR®
`58
`2004
`
`EDITION
`
`Ys A\
`D
`T
`
`\C 0
`
`Executive Vice President, Directory Services: David Duplay
`
`Vice President, Sales and Marketing: Dikran N. Barsarhian
`Senior Director of Pharmaceutical Sales: Anthony Sorce
`National Account Manager: Marion Reid, RPh
`Senior Account Manager: Frank Karkowsky
`Account Managers: Marjorie A. Jaxel, Denise Kelley, Eileen Sullivan,
`Suzanne E. Yarrow, RN
`Director of Trade Sales: Bill Gaffney
`Senior Director, Marketing and Product Management:
`Valerie E. Berger
`Senior Product Manager: Jeffrey D. Dubin
`Finance Director: Mark S. Ritchin
`Senior Director, Publishing Sales and Marketing: Michael Bennett
`Senior Marketing Manager: Jennifer M. Fronzaglia
`Direct Mail Manager: Lorraine M. Loening
`Manager of Marketing Analysis: Dina A. Maeder
`Promotion Manager: Linda Levine
`Vice President, Regulatory Affairs: Mukesh Mehta, RPh
`Editorial Director: Lisette Bralow
`Manager, Professional Data Services: Thomas Fleming, PharmD
`Manager, Editorial Services: Bette LaGow
`Manager, Concise Data Content: Tammy Chernin, RPh
`
`Drug Information Specialists: Greg Tallis, RPh; Min Ko, PharmD
`Project Editor: Harris Fleming
`Senior Editor: Lori Murray
`Production Editor: Gwynned L. Kelly
`Senior Director, Operations: Brian Holland
`Director of PDR Operations: Jeffrey D. Schaefer
`Manager of Production Operations: Thomas Westburgh
`PDR Production Manager: Joseph F. Rizzo
`Senior Production Coordinators: Gianna Caradonna, Christina Klinger
`Production Coordinator: Yasmin Hernandez
`Senior Index Editor: Shannon Reilly
`Index Editor: Noel Deloughery
`Format Editor: Michelle S. Guzman
`Production Associate: Joan K. Akerlind
`Production Design Supervisor: Adeline Rich
`Electronic Publishing Designers: Bryan Dix, Rosalia Sberna, Livio Udina
`Digital Imaging Coordinator: Michael Labruyere
`Director of Client Services: Stephanie Struble
`Fulfillment Manager: Louis J. Bolcik
`
`-ruic, M S CII INJ
`
`Copyright 2004 and published by Thomson PDR at Montvale, NJ 07645-1742. All rights resented. None of the content of this publication
`may be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical,
`photocopying, recording, or otherwise) without the prior written permission of the publisher. Physicians* Desk Reference., PDR., Pocket
`PER
`PDR°, PDR Family Guide to Prescription Drugs., PDR Family Guide to Women's Health and Prescription Drugs°, and PDR Family Guide to
`Nutrition and Health° are registered trademarks used herein under license. PDR° for Ophthalmic Medicines, PDR° for Nonprescription Drugs and Dietary Supplements, PCIR.
`Companion Guide, POW Pharmacopoeia, PDR° for Herbal Medicines, PDR° for Nutritional Supplements, PDR° Medical Dictionary, PDR° Nurse's Drug Handbook, PDR°
`Nurse's Dictionary, PDR° Family Guide Encyclopedia of Medical Care, PDR° Family Guide to Natural Medicines and Healing Therapies, PDR° Family Guide to Common
`Ailments, PDR° Family Guide to Over-the-Counter Drugs, PDR° Family Guide to Nutritional Supplements, and PDR° Electronic Library are trademarks used herein under
`license.
`
`Officers of Thomson Healthcare,: President and Chief Executive Officer: Richard Noble; Chief Financial Officer Paul Hilger; Executive Vice President, Clinical Trials: Tom Kelly;
`Executive Vice President, Medical Education: Jeff MacDonald; Executive Vice President, Clinical Solutions: Jeff Reihl; Executive Vice President, Directory Services: David Duplay;
`Senior Vice President, Business Development: William Gole; Vice President, Human Resources: Pamela M. Bilash; President, Physician's World: Marty Cearnal
`
`ISBN: 1-56363-471-6
`
`

`

`PHYSICIANS' DESK REFERENCE®
`
`Buprenorphine is a Schedule III narcotic under the Con-
`trolled Substances Act.
`Buprenorphine hydrochloride is a white powder, weakly
`acidic with limited solubility in water (17mg/mL).
`Chemically, buprenorphine is 17-(cyclopropylmethyl)-a-(1,1-
`dimethylethyl)-4, 5-epoxy-18, 19-dihydro-3-hydroxy-6-
`methoxy-a-methy1-6, 14-Othenomorphinan-7-methanol,
`hydrochloride [5a, 7a(S)]-. Buprenorphine hydrochloride
`has the molecular formula C,01141NO,1-ICI and the molecu-
`lar weight is 504.10.
`
`HO
`
`NJ>
`
`CH,0
`
`CH,
`
`C(CH,),
`.HCI
`Naloxone hydrochloride is a white to slightly off-white
`powder and is soluble in water, in dilute acids and in strong
`alkali. Chemically, naloxone is 17-AllyI-4,5 a-epoxy-3, 14-
`dihydroxymorphinan-6-one hydrochloride. Naloxone hydro-
`chloride has the molecular formula C,,H,,NO,HCI .21-1,0
`and the molecular weight is 399.87.
`
`HO
`
`• Ha. 2 Hp
`
`than placebo (3 hour AUC values). Minimum and maximum
`effects were similar across all treatments. Subjects re-
`mained responsive to low voice and responded to computer
`prompts. Some subjects showed irritability, but no other
`changes were observed.
`The respiratory effects of sublingual buprenorphine were
`compared with the effects of methadone in a double-blind,
`parallel group, dose ranging comparison of single doses of
`buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg)
`and oral methadone (15, 30, 45, or 60 mg) in non-dependent,
`opioid-experienced volunteers. In this study, hypoventila-
`tion not requiring medical intervention was reported more
`frequently after buprenorphine doses of 4 mg and higher
`than after methadone. Both drugs decreased 0, saturation
`to the same degree.
`Effect of Naloxone:
`Physiologic and subjective effects following acute sublingual
`administration of SUBOXONE and SUBUTEX tablets were
`similar at equivalent dose levels of buprenorphine.
`Naloxone, in the SUBOXONE formulation, had no clinically
`significant effect when administered by the sublingual
`route, although blood levels of the drug were measurable.
`SUBOXONE, when administered sublingually even to an
`opioid-dependent population, was recognized as an opioid
`agonist, whereas when administered intramuscularly, com-
`binations of buprenorphine with naloxone produced opioid
`antagonist actions similar to naloxone. In methadone-main-
`tained patients and heroin-dependent subjects, intravenous
`administration of buprenorphine/naloxone combinations
`precipitated opioid withdrawal and was perceived as un-
`pleasant and dysphoric. In morphine-stabilized subjects, in-
`travenously administered combinations of buprenorphine
`with naloxone produced opioid antagonist and withdrawal
`effects that were ratio-dependent; the most intense with-
`drawal effects were produced by 2:1 and 4:1 ratios, less in-
`tense by an 8:1 ratio. SUBOXONE tablets contain
`buprenorphine with naloxone at a ratio of 4:1.
`Pharmacokinetics:
`0
`Absorption:
`Plasma levels of buprenorphine increased with the sublin-
`SUBOXONE is an uncoated hexagonal orange tablet in-
`gual dose of SUBUTEX and SUBOXONE, and plasma levels
`tended for sublingual administration. It is available in two
`of naloxone increased with the sublingual dose of
`SUBOXONE (Table 1). There was a wide inter-patient vari-
`dosage strengths, 2mg buprenorphine with 0.5rog naloxone,
`ability in the sublingual absorption of buprenorphine and
`and 8mg buprenorphine with 2mg naloxone free bases.
`naloxone, but within subjects the variability was low. Both
`Each tablet also contains lactose, mannitol, cornstarch, po-
`Cr,,.„. and AUC of buprenorphine increased in a linear fash-
`vidone K30, citric acid, sodium citrate, FD&C Yellow No.6
`ion with the increase in dose (in the range of 4 to 16 mg),
`color, magnesium stearate, and the tablets also contain
`although the increase was not directly dose-proportional.
`Acesulfame K sweetener and a lemon/lime flavor.
`Naloxone did not affect the pharmacokinetics of
`SUBUTEX is an uncoated oval white tablet intended for
`buprenorphine and both SUBUTEX and SUBOXONE de-
`sublingual administration. It is available in two dosage
`liver similar plasma concentrations of buprenorphine. The
`strengths, 2mg buprenorphine and 8mg buprenorphine free
`levels of naloxone were too low to assess dose-proportional-
`base. Each tablet also contains lactose, mannitol, corn-
`ity. At the three naloxone doses of 1 mg, 2 mg, and 4 mg,
`starch, povidone K30, citric acid, sodium citrate and mag-
`levels above the limit of quantitation (0.05 ng/mL) were not
`detected beyond 2 hours in seven of eight subjects. In one
`nesium stearate.
`individual, at the 4mg dose, the last measurable concentra-
`CLINICAL PHARMACOLOGY
`tion' was at 8 hours. Within each subject (for most of the
`•
`Subjective Effects:
`subjects), across the doses there was a trend toward an in-
`Comparisons of buprenorphine with full agonists such as
`crease in naloxone concentrations with increase in dose.
`methadone and hydromorphone suggest that sublingual bu-
`Mean peak naloxone levels ranged from 0.11 to 0.28ng/m1 in
`prenorphine produces typical opioid agonist effects which
`the dose range of 1-4 mg.
`are limited by a ceiling effect.
`In non-dependent - subjects, acute sublingual doses of
`[See table 1 below]
`SUBOXONE tablets produced opioid agoaist effects, which
`Distribution:
`Buprenorphine is approximately 96% protein bound, pri-
`reached a maximum between doses of 8 mg and 16mg of
`marily to alpha and beta globulin.
`SUBUTEX. The effects of 16mg SUBOXONE were similar
`Naloxone is approximately 45% protein bound, primarily to
`to those produced by 16mg SUBUTEX (buprenorphine
`albumin.
`alone).
`Metabolism:
`Opioid agonist ceiling effects were also observed in a double-
`Buprenorphine undergoes both N-dealkylation to norbu-
`blind, parallel group, dose ranging comparison of single
`prenorphine and glucuronidation. The N-dealkylation path-
`doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or
`way is mediated by cytochrome P-450 3A4 isozyme. Norbu-
`32 mg), placebo, and a full agonist control at various doses.
`prenorphine, an active metabolite, can further undergo
`The treatments were given in ascending dose order at inter-
`glucuronidation.
`vals of at least one week to 1.6 opioid-experienced, non-
`Naloxone undergoes direct glucuronidation to naloxone
`dependent subjects. Both drugs produced typical opioid
`3-glucuronide as well m N-dealkylation, and reduction of
`agonist effects. For all the measures for which the drugs
`the 6-oxo group.
`produced an effect, buprenorphine produced a dose-related
`Elimination:
`response but, in each case, there was a dose that produced
`Amass balance study of buprenorphine showed complete re-
`no further effect. In contrast, the highest dose of the full
`covery of radiolabel in urine (30%) and feces (69%) collected
`agonist control always produced the greatest effects. Ago-
`up to 11 days after dosing. Almost all of the dose was ac-
`nist objective rating scores remained elevated for the higher
`counted for in terms of buprenorphine, norbuprenorphine,
`doses of buprenorphine (8-32 mg) longer than for the lower
`and two unidentified buprenorphine metabolites. In urine,
`doses and did not return to baseline until 48 hours after
`most of buprenorphine and norbuprenorphine was conju-
`drug administrations. The onset of effects appeared more
`gated (buprenorphine, 1% free and 9.4% conjugated; norbu-
`rapidly with buprenorphine than with the full agonist con-
`prenorphine, 2.7% free and 11% conjugated). In feces, al-
`trol, with most doses nearing peak effect after 100 minutes
`most all of the buprenorphine and norbuprenorphine were
`for buprenorphine compared to 150 minutes for the full ag-
`free (buprenorphine, 33% free and 5% conjugated; norbu-
`onist control.
`prenorphine, 21% five and 2% conjugated).
`•
`Physiologic Effects:
`Buprenorphine has a mean elimination half-life from
`Buprenorphine in intravenous (2mg, 4mg, 8mg, 12mg and
`plasma of 37 h.
`16 mg) and sublingual (12mg) doses has been administered
`Naloxone has a mean elimination half-life from plasma of
`to non-dependent subjects to examine cardiovascular, respi-
`ratory and subjective effects at doses comparable to those
`1.1 h.
`Special Populations:
`used for treatment of opiciid dependence. Compared with
`Hepatic Disease:
`placebo, there were no statistically significant differences
`The effect of hepatic impairment on the pharmacokinetics of
`among any of the treatment conditions for blood pressure,
`buprenorphine and naloxone ie unknown. Since both drugs
`heart rate, respiratory rate, 02 saturation or skin tempera-
`are extensively, metabolized, the plasma levels will be ex-
`ture across time. Systolic BP was higher in the 8 mg group
`Table 1. Pharmacoldnetic parameters of buprenorphine after the administration of 4 mg, 8mg, and 16 mg Suboxone®
`doses and 16mg Subutex® dose (mean (%CV))
`
`2866/RECKITT BENCKISER
`
`Buprenex—Cont.
`
`TIVE IN REVERSING THE RESPIRATORY DEPRESSION
`PRODUCED BV BUPRENEX. THEREFORE, AS WITH OTHER
`POTENT OPIOIDS, THE PRIMARY MANAGEMENT OF
`OVERDOSE SHOULD BE THE REESTABLISHMENT OF AD-
`EQUATE VENTILATION WITH MECHANICAL ASSISTANCE
`OF RESPIRATION, IF REQUIRED.
`DOSAGE AND ADMINISTRATION
`Adults: The usual dosage for persons 13 years of age and
`Buprenex (0.3 mg buprenorphine) given by deep
`over is 1
`intramuscular or slow (over at least 2 minutes) intravenous
`injection at up to 6-hour intervals, as needed. Repeat once
`(up to 0.3 mg) if required, 30 to 60 minutes after initial dos-
`age, giving consideration to previous dose pharmacokinet-
`ics, and thereafter only as needed. In high-risk patients
`(e.g., elderly, debilitated, presence of respiratory disease,
`etc.) and/or in patients where other CNS depressants are
`present, such as in the immediate postoperative period, the
`dose should be reduced by approximately one-half. Extra
`caution should be exercised with the intravenous route of
`administration, particularly with the initial dose.
`Occasionally, it may be necessary to administer single doses
`of up to 0.6 mg to adults depending on the severity of the
`pain and the response of the patient. This dose should only
`be given I.M. and only to adult patients who are not in a
`high risk category (see WARNINGS and PRECAUTIONS).
`At this time, there are insufficient data to recommend single
`doses greater than 0.6 mg for long-term use.
`Children: Buprenex has been used in children 2-12 years
`of age at doses between 2-6 micrograms/kg of hody weight
`given every 4-6 hours. There is insufficient experience to
`recommend a dose in infants below the age of two years,
`single doses greater than 6 micrograms/kg of body weight,
`or the use of a repeat or second dose at 30-60 minutes (such
`as is used in adults). Since there is some evidence that not
`all children clear buprenorphine faster than adults, fixed in-
`terval or "round-the-clock" dosing should not be undertaken
`until the proper inter-dose interval has been established by
`clinical observation of the child. Physicians should recog-
`nize that, as with adults, some pediatric patients may not
`need to be remedicatecl for 6-8 hours.
`Safety and Handling: Buprenex is supplied in sealed am-
`pules and poses no known environmental risk to health care
`providers. Accidental dermal exposure should be treated by
`removal of any contaminated clothing and rinsing the af-
`fected area with water.
`Buprenex is a potent narcotic, and like all drugs of this class
`has been associated with abuse and dependence among
`health care providers. To control the risk of diversion, it is
`recommended that measures appropriate to the health care
`aetting be token to provide rigid accounting, control of wast-
`age, and restriction of access.
`Parenteral drug products should be inspected visually for
`particulate matter and discoloration prior to administra-
`tion, whenever solution and container permit.
`HOW SUPPLIED
`Buprenex (buprenorphine hydrochloride) is supplied in
`clear glass snap-ampule of 1 ml (0.3 mg buprenorphine).
`NDC 12496-0757-1
`Avoid excessive heat (over 104°F or 40°C). Protect from pro-
`•
`longed exposure to light.
`Manufactured by:
`Reckitt Benckiser Healthcare (UK) Ltd
`Hull, England HU8 7DS
`UK
`Distributed by:
`Reckitt Benckiser Pharmaceuticals Inc.
`Richmond, VA 23235
`Buprenex ® is a trademark of Reckitt & Colman (Overseas)
`Limited.
`REVISED November 2002
`Shown in Product Identification Guide, page 333
`
`€
`
`SUBOXONE
`[sabox'One]
`(buprenorphine HCI and naloxone HCI dihydrate
`sublingual tablets)
`SUBUTEX
`isab'Stex]
`(buprenorphine HCI sublingual tablets)
`134 only
`Under the Drug Addiction Treatment Act of 2000 (DATA)
`codified at 21 U.S.C. 823(g), prescription use of this product
`in the treatment of opioid dependence is limited to physi-
`cians who meet certain qualifying requirements, and have
`notified the Secretary of Health and Human Services (HHS)
`of their intent to prescribe this product for the treatment of
`opioid dependence.
`DESCRIPTION
`SUBOXONE sublingual tablets contain buprenorphine HCI
`and naloxone HCI dihydrate at a ratio of 4:1 buprenorphine:
`naloxone (ratio of free bases).
`SUBUTEX sublingual tablets contain buprenorphine HCL
`Buprenorphine is a partial agonist at the mu-opioid recep-
`tor and an antagonist at the kappa-opioid receptor.
`Naloxone is an antagonist at the mu-opioid receptor.
`
`Pharmacokinetic Parameter
`
`Cu,,,‚ ng/mL
`
`AUC, houeng/mL
`
`Suboxonee
`4mg
`
`1.84 (39)
`
`12.52 (35)
`
`Suboxonee
`8mg -
`
`3.0 (51)
`
`20.22 (43)
`
`Suboxonee
`mg
`16
`
`5.95 (38)
`
`34.89 (33)
`
`SubuteMB
`16 mg
`
`- 5.47 (23)
`
`32.63 (25)
`
`Information will be superseded by supplements and subsequent edrtions
`
`

`

`PRODUCT INFORMATION
`
`RECKITT BENCKISER/2867
`
`petted to be higher in patients with moderate and severe
`hepatic impairment. However, it is not known whether both
`drugs are affected to the same degree. Therefore, in patients
`with hepatic impairment dosage should be adjusted and pa-
`tients should be observed for symptoms of precipitated
`opioid withdrawal.
`Renal Disease:
`No differences in buprenorphine pharmacokinetics were
`observed between 9 dialysis-dependent and 6 normal
`patients following intravenous administration of 0.3mg
`buprenorphine.
`The effects of renal failure on naloxone pharmacokinetics
`are unknown.
`Drug-drug interactions:
`CYP 3A4 Inhibitors and Inducers: A pharmacokinetic in-
`teraction study of ketoconazole (400 mg/day), a potent
`inhibitor of CYP 3A4, in 12 patients stabilized on
`SUBOXONE l8mg (n=1) or 12mg (n.5). or 16mg (n=6)l re-
`sulted in increases in buprenorphine mean Cmax values
`(from 4.3 to 9.8, 6.3 to 14.4 and 9.0 to 17.1) and-mean AUC
`values (from 30.9 to 46.9, 41.9 to .83.2 and 52.3 to 120) re-
`spectively. Subjects receiving SUBUTEX or SUBOXONE
`should be closely monitored and may require dose-reduction
`if inhibitors of CYP 3A4 such as azole antifungal agents
`(e.g. ketoconazole), macrolide antibiotics (e.g., erythromy-
`cin) and HIV protease inhibitors (e.g. ritonavir, indin.avir
`and saquinavir) are co-administered. The interaction of
`buprenorphine with CYP 3A4 inducers has not been inves-
`tigated; therefore it is recommended that patients receiving
`SUBUTEX or SUBOXONE should be closely monitored if
`inducers of CYP 3A4 (e.g. phenobarbital, carbainazepine,
`phenytoin, rifampicin) are co-administered (SEE WARN-
`INGS).
` .
`•
`CLINICAL STUDIES
`Clinical data on the safety and efficacy of SUBOXONE and
`SUBUTEX are derived from studies of buprenorphine sub-
`lingual tablet formulations, with and without naloxone, and
`from studies of sublingual administration of a more bio-
`available ethanolic solution of buprenorphine..
`SUBOXONE tablets have been studied in 575 patients,
`SUBUTEX tablets in 1834 patients and buprenorphine sub-
`lingual solutions in 2470 patients. A total of 1270 females
`have received buprenorphine -in clinical trials. Dosing rec-
`ommendations are based on data from one trial of both
`tablet formulations and two trials of the ethanolic solution.
`All trials used buprenorphine in conjunction with psychoso-
`cial counseling as part of a comprehensive addiction treat-
`ment program. There have been no clinical studies con-
`ducted to assess the efficacy Of buprenorphine as the only
`component of treatment.
`In a double blind placebo- and active controlled study, 326
`heroin-addicted .subjects were randomly assigned to either
`SUBOXONE 16 mg per day, 16 mg SUBUTEX per day .or
`placebo tablets. For subjects randomized to either active
`treatment, dosing began with one 8 mg tablet of SUBUTEX
`on Day 1, followed by 16 mg (two .8 mg tablets) of SUBUTEX
`on Day 2. On Day 3, those randomized to receive
`SUBOXONE were switched to the combinationtablet. Sub-
`jects randomized to placebo received one placebo tablet on
`Day 1 and two placebo tablets per day thereafter for four
`weeks. Subjects were seen. daily in the clinic (Monday
`through Friday) for dosing and efficacy assessments. Take-
`home doses were provided for weekends. Subjects were in,
`structed to hold the medication under the tongue for ap-
`proximately 5 to 10 minutes until completely dissolved.
`Subjects received one hour of individual counseling per
`week and a single session of HIV education. The primary
`study comparison was to assess the efficacy. of SUBUTEX
`and SUBOXONE individually. against placebo. The percent-
`age. of thrice-weekly urine samples. that were negative
`for non-study opioids was statistically higher for both
`SUBUTEX and SUBOXONE, than for placebo.
`In a double-blind, double-dummy, parallel-group study min-
`paring buprenorphine ethanolic solution to a full agonist ac-
`tive control, 162 subjects were randomized to receive the
`ethanolic sublingual solution of buprenorphine at 8 mg/day
`(a dose which is roughly comparable to adose of 12 mg/day
`of SUBUTEX or SUBOXONE), or two relatively low doses of
`active control, one of which was low .enough to serve as an
`alternative to placebo, during a 3-10 day induction phase, a
`16-week maintenance phase and a 7-week detoxification
`phase. Buprenorphine was titrated to maintenance dose by
`Day 3; active control doses were titrated more gradually. '
`Maintenance dosing continued through Week 17, and then
`medications were tapered by approximately 20-30% per
`week over Weeks 18-24, with placebo dosing for the last two
`weeks. Subjects received individual and/or group counseling
`weekly.
`Based on retention in treatment and the percentage of
`thrice-weekly urine samples negative for non-study opioids,
`buprenorphine .was more effective than the low dose of the
`control, in keeping heroin addicts in treatment and in re-
`ducing their use of opioids while in treatment The effective-
`ness of buprenorphine, 8 mg per day was similar to that of
`the moderate active control dose, but equivalence was not
`•
`demonstrated.
`In a dose-controlled, double-blind, parallel-group, 16-week
`study, 731 subjects were randomized to receive one of four
`doses of buprenorphine ethanolic solution. Buprenorphine
`was titrated to maintenance doses over 1-4 days (Table 2)
`and continued for 16 weeks. Subjects received at least one
`session of AIDS education and additional counseling rang-
`nig from one hour per month to one hour per week, depend-
`ing on site.
`
`Table 2. Doses of Sublingual Buprenorphine Solution used
`for Induction in a Double-Blind Dose Ranging Study
`
`Target Dose of
`Buprenorphine.
`
`1 mg
`
`4 mg
`
`8 mg
`
`Induction Dose
`
`Day 1 Day 2 Day 3
`
`1 mg
`
`1 mg.
`
`1 mg
`
`2 mg 4 mg 4 mg
`
`2 mg 4 mg 8 mg
`
`Maintenance
`dose
`
`1 mg
`
`4 mg
`
`8 mg
`
`16 mg
`
`2 mg 4 mg 8 mg
`
`16 mg
`
`°Sublingual solution. Doses in this table cannot necessarily
`be delivered in tablet form, but for comparison purposes:
`2 mg solution would be roughly equivalent to 3 mg tablet
`4 mg solution would be roughly equivalent to 6 mg tablet
`8 mg solution would be roughly equivalent to 12 mg tablet
`16 mg solution would be roughly equivalent to 24 mg tablet
`
`Based on retention in treatment and the percentage of
`thrice:weekly urine samples negative for non-study opioids,
`the three- highest tested doses were superior to the
`lmg dose. Therefore, this study showed that a .range of
`bupreriorphinedeses may be effective. The lmg dose of
`buprenorphine sublingual 'solution can be considered to be
`somewhat loWer than a 2 mg tablet dose. The other doses
`used in the study encompass a range of tablet doses from
`approximately 6 mg to approximately 24 mg.
`•
`
`•
`INDICATIONS AND USAGE
`SUBOXONE and SUBUTEX are indicated for the treat-
`ment of opioid dependence. •- .
`CONTRAINDICATIONS'
`SUBOXONE aiad SUBUTEX should not be administered to
`patients who have been shown to be hypersensitive to
`buprenorphine, and. SUBOXONE should not be adminis-
`tered to patients who have been shown to be hypersensitive
`.
`to naloxone.:
`WARNINGS
`Respiratory Depression:
`Significant respiratory depression has been associated with
`buprenorphine, particularly by the intravenous -route. A
`number of deaths have occurred when addicts have intrave-
`nously misused buprenorphine; usually with benzodiaz-
`epines concomitantly. Deaths have also been reported
`in association with concomitant administration of
`buprenorphine with other depressants such as alcohol or
`other opioids. Patients should be warned of the potential
`danger -of the self-administration of benzodiazepines or
`other depressants while under treatment with SUBUTEX
`or SUBOXONE.
`IN THE CASE OF OVERDOSE, THE PRIMARY MANAGE-
`MENT SHOULD BE THE RE-ESTABLISHMENT OF AD-
`EQUATE VENTILATION WITH MECHANICAL ASSIS-
`TANCE OF RESPIRATION, IF REQUIRED. NALOXONE
`MAY NOT BE EFFECTIVE IN REVERSING ANY
`RESPIRATORY DEPRESSION PRODUCED BY
`BUPRENORPHINE.
`SUBOXONE and SUBUTEX should be used with caution in
`patients with comproinised respiratory function (e.g.,
`chronic obstructive pulmonary disease, cor pulmonale, de-
`creased respiratory reserve, hynoxia, hypercapnia, or pre-
`existing respiratory depression).
`CNS Depression:
`. .
`Patients receiving buprenorphine in the presence of other
`narcotic analgesics, general anesthetics, benzodiazepines,
`phenothiarines, other tranquilizers, sedative/hypnotics or
`other CNS depressants (including alcohol) may exhibit in-
`creased:CMS depression. When such combined therapy is
`contemplated, redUction of the dose of one or both agents
`•
`should be considered.
`Dependence:
`Buprenorphine is a partial agonist at the mu-opiate recep-
`tor and chronic administration produces dependence of the
`opioid type, characterized by withdrawal upon abrupt dis-
`continuation or rapid taper. The withdrawal syndrome is
`milder than seen with full agonists, and may be delayed in
`onset • .•
`Hepatitis, hepatic events:
`Cases of cytolytic hepatitis and hepatitis with jaundice
`have been • observed in the addict population receiving
`buprenorphine both in clinical trials and in post-marketing
`adverse event reports. The spectrum of abnormalities
`ranges from transient asymptomatic elevations in hepatic
`transaminases to case reports of hepatic failure, hepatic ne-
`croais; hepatorenal syndrome, and hepatic encephakmathy.
`In many cases, the presence of pre=existing liver enzyme ab-
`normalities, infection with h'epatitis B or hepatitis C virus,
`concothitant usage of other 'potentially liepatotoxic drugS,'
`and ongoing injecting drug use may have played a causative
`or contributory tole. In other cases; insufficient data were
`available to determine the etiology of the abnormality. The
`poisibility exists that huirenorphine had a causative or
`contributory role in the dev.elopment of the hepatic abnor-
`mality in some cases. Measurements of liver function tests
`prior to initiation oftreatnient is recommended to establish
`a baseline. Periodic monitoring of liver function tests during
`treatment is also recommended. A biological and etiological
`evaluation is recommended when a hepatic event is sus-
`pected. Depending on the case, the drug should be carefully
`
`discontinued to prevent withdrawal symptoms and a return
`to illicit drug use, and strict monitoring of the patient
`should be initiated.
`Allergic Reactions:
`Cases of acute and chronic hypersensitivity to
`buprenorphine have been reported both in clinical trials and
`in the post-marketing experience. The most common signs
`and symptoms include rashes, hives, and pruritus. Cases of
`bronchospasm, angioneurotic edema, and anaphylactic
`shock have been reported. A history of hypersensitivity to
`buprenorphine is a contraindication to Subutex or Suboxone
`use. A history of hypersensitivity to naloxone is a contrain-
`dication to &Moran* use.
`Use in Ambulatory Patients:
`SUBOXONE and SUBUTEX may impair the mental or
`physical abilities required for the performance of potentially
`dangerous tasks such as driving a car or operating machin-
`ery, especially during drug induction and dose adjustment.
`Patients should be cautioned about operating hazardous
`machinery, including automobiles, until they are reasonably
`certain that buprenorphine therapy does not adversely af-
`fect their ability to engage in such activities. Like other opi-
`oids, SUBOXONE and SUBUTEX may produce orthostatic
`hypotension in ambulatory patients.
`Head Injury and Increased lntracranial Pressure:
`SUBOXONE and SUBUTEX, like other potent opioids, may
`elevate cerebrospinal fluid pressure and should be used
`with caution in patients with head injury, intracranial le-
`sions and other circumstances where cerebrospinal pressure
`may be increased. SUBOXONE and SUBUTEX can produce
`miosis and changes in the level of consciousness that may
`interfere with patient evaluation.
`Oploid withdrawal effects:
`•
`.
`Because it contains. naloxone, SUBOXONE is highly likely
`to produce marked and intense withdrawal symptoms if
`misused parenterally by individuals dependent on opioid
`agonists such as heroin, morphine, or methadone. Sublin-
`gually, SUBOXONE may cause opioid withdrawal symp-
`toms in such persons if administered before the agonist ef-
`fects of the opioid have subsided.
`
`PRECAUTIONS
`General:
`SUBOXONE and SUBUTEX should be administered with
`caution in elderly or debilitated patients and those with se-
`vere impairment of hepatic, pulmonary, or renal function;
`myxedema or hypothyroidism, adrenal cortical insufficiency
`(e.g., Addison's disease); CNS depression or coma; toxic psy-
`choses; prostatic hypertrophy or urethral stricture; acute al-
`coholism; delirium tremens; or kyphoscoliosis.
`The effect of hepatic impairment on the pharmacokinetics of
`buprenorphine and naloxone is unknown. Since both drugs
`are extensively metabolized, the plasma levels will be ex-
`pected to be higher in patients with moderate and severe
`hepatic impairment. However, it is not known whether both
`drugs are affected to the same degree. Therefore, dosage
`should be adjusted and patients should be watched for
`symptomsuf precipitated opioid withdrawal.
`Buprenorphine has been shown to increase intrachole-
`dochal pressure, as do other opioids, and thus should be ad-
`ministered with caution to patients with dysfunction of the
`biliary tract.
`As with other mu-opioid receptor agonists, the administra-
`tion of SUBOXONE or SUBUTEX may obscure the diagno-
`sis or clinical course of patients with acute abdominal
`conditions.
`Drug Interactions:
`Buprenorphine is metabolized to norbuprenorphine by cyto-
`chrome CYP 3A4. Because CYP 3A4 inhibitors may increase
`plasma concentrations of buprenorphine, patients already
`on CYP 3A4 inhibitors such as azole antifungals (e.g. keto-
`conazole), macrolide antibiotics (e.g. erythromycin), and
`HIV protease inhibitors (e.g. ritonavir, indinavir and
`saquinavir) should have their dose of SUBUTEX or
`SUBOXONE adjusted.
`Based on anecdotal reports, there may be an interaction be-
`tween buprenorphine and benzodiazepines. There have
`been a num