_
`(cm)
`(buprenorphine HCl and naloxone HUI dlhydrate sublingual tablets)
`(C111)
`(buprenorphine HCi subllngual tablets)
`
`Under the Drug AdcfictionTreatinent Act oi limit {QATIAJ codified at at U.S.C. 323$}. prescription use at
`this product in the treatment at opioid dependence is limited to pl
`ictIans who or
`certain tlLIilitiyii‘lQ
`requirements and have notified the Secretary otitoatlh and Human moss [Hi-i5} at their intent to prescribe
`this product ior ma iii-Batmaitt oi opioid dependence.
`I
`I
`.
`SUBOXONE sublingual tablets contain buprenorphine HCI and naioxone HCI dihydrate at a ratio oi 4:1
`buprenorphine: natoxone (ratio at tree bases).
`SUBUTEX sublingual tablets contain buprenorphine HCl.
`
`Buprenorphine is a partial a onist at theInIiu-opiotd receptor and an antagonist at the kappaopioid receptor.
`Na oxene is an aniagontsta the mu-oprord remptor.
`Buprenorphlne is a Schedule Iii narcotic under the Controlled Substances Act.
`
`Bupronorphinc hydrochloride is Ia white powder.
`wenieyaddbwitii iriitedsot
`rnvntot'l'i'rnry'rnti.
`Chemically. buprono
`itneist «(cyctoprgflidmothygi
`n-ttJ-dlmethidlethyi
`.5-e
`xii-13.1
`itiydro .
`i droxy-Ermo
`-o-me
`-fi.14-
`I
`e
`omorpiilnan- niatha
`.li drocirtondeitiri.
`rag. Bupreno hineli
`rocti
`ridetiasthe
`mI
`iartomwlalgmtin
`HCiandtherndocutar
`W9Ighli55fld.10.
`STRUCTURAL FORMULA 0F BUPRENOR PHiNE
`
`
`
`.HCI
`with
`drocitioride is a ntrite to slightly oii‘
`Naioirone
`while new er and is soiubie in water. in dliute acids
`and in strong alkali. Chemical
`.natoxoiie is. 1?-
`Aiiyi-rifs u
`_
`. ill-mi
`ro
`urpitintill-E'
`one hydrocir
`n e. Naloiiorie Hy rociiloriitetras the
`molecular tonjnuiaI C it
`tit}. l-iBt an. t) and the
`molecutarweigtit is dieii‘r
`
`STRUCTURAL FORMULA 0F NALOXONE
`
` .HCi
`
`SUBDXt‘iNE is an nncotitod hexagonal orange tattle! intended for subiiiigual administration. Itis
`ire
`amiable in two dosage strengths. 2m buprenorphine with ofimg naloxune. and time tiupreno
`\tti'llil 2m notorious tree bases. Each to 3hr also contains lactose. nrarinitoi. comstanit. powdone git}.
`citric ac . sodium citrate. FD 8.6 Yellow No.5 color. rriepnestum steamto. end the tablets. also coritam
`Acosultame it sweetener and a lemonir time tlairor.
`
`SUBUTEX is an uncoatod oval whibt tablet intended for subiingnal administration. It is available in two
`dosage strengths. 2mg huprano hina and time bu rend hint: tree base. Each tablutalsri contains lactose.
`mannitoL cometarcli. povidone i250. citric acid. sotignnn ciii‘aie and manrresiurn steeratc
`
`
`
`CLINIICAL PHARMACOLOGY
`I
`Sub/active Effects:
`Comparisons of buprenorphine with lull a onists such as methadone and hydromorphone suggest that
`sublinguat buprenorphine produces typ'
`opioid agonist eiiects which are imited by a ceiling eiiect.
`In non-dependentsui'riects acute subtingual doses of SUBOXONE tablets
`roduced opioid agonist etiecis.
`which reached a maximum between doses at 8 or and 16mg oiStJBUTEX
`etiecw oi 16mg SUBOXONE
`were similar to those produced by 15mg SUB
`(buprenorphine alone).
`
`opera agoniatrelilng sheets were alsoIobsenred in a doubiebilndfiraraitel group. dose ranging comparison
`o stunts doses at buprenorphine sublinnoal solution {1. 2.41 IB.1 . or 32 mg? placebo. and it tuit agonist
`miniol atrianous doses. The treatments were given In ascending dose ordcraI intanfais of at least one week
`to 16 opioidstiroenenced riondependent sob
`. Both drugs produced nrpital opioid aoonlsl ettcctsfor
`all the measures torwhicii the drugs produ
`an silent. buprenorphine produced a dose-related response
`but in each case there was a dose that produced no iuriirerettecl. in contrast. the highest dose of the lull
`agonist control aiways produced the
`realest effects. Anorrist obtectnrc rating scores remained elevated tor
`die hi herdoses oi buprenorphine i'
`2 mo} longer titan tor the bitter dosesandIdid not return to baseline
`until
`I hours alter drug administra tons. The onset oi attests appeared more rapidly wit: buprenorphine
`titan With the toil agonisi control. with most doses nearing peak ellect after 100 minutes tor tarpienorplilna
`compared to 150 minutes tor the lull agonist control.
`
`.
`Pnyeioioglefllam:
`)and sublrnpuat 12mg} doses has heart
`Bupmnotphlne in inimianous tamggtmg. 3mg. 12mg and 16
`administered to non dependent on roots to examine cardiovastai 1r. rcspimiory a I subtractive eiiocts at
`doses oomparabieto tltoso used tor treatment at 0 lord do
`ndenoe. Compared wrth placebo. there were
`no statistically s niiiotint dilierenoecamong any
`the tree menl conditions tor blood pressure. heart rate.
`respiratory rate.
`saturation or strinItempcr'alure across time. Systolic BP was higher in the 3 mo group
`than placebo (3 hourAUC retires . Minimum and maximum ettects were similar across all treatments.
`Sealants remained responsnro to ow voice and responded to computerprompts. Some subtracts showed
`irritability: but no other changes were observed.
`
`The res ratory slices; of subliriuuai buprenorphine were compared with the eiiects oi mediadone in a I
`double lind parallelgroup. dose mugs oornpanson oi sinuslgidoses of buprenorphine subtirigual solution
`it . 2. a, e. is. or 32 to ram oral on.
`one{15.3t].45.tu'
`mg) In nun-dependent. opioid-exponettccd
`volunteers. In this slu . liypoventriatron not
`uir'in medical intervention was receded more lrenuer'ilty
`agifir‘éruprengrphlna doses old my and i'e'giiert tan a on methadone. Both drugs decreased 0.; saturaton
`same agree.
`Elise! ot' mimetic:
`Physioiogic and subjective eilecls lotiowin acute sublingual administration at SUBDXONE and SUBUTEX
`tab etsnorc similar at enuhralent decal
`5 ct buprenu hlne. itiaioirone. In the SUBOXONE iormutation.
`had no dinitatiy e nllioant ottoct when administered 1:
`a setting ual route. alti'Iiougii blood levels at the
`data were measu
`let SlIiBOXDNE. when adrniriLs
`subiirrgtal Ieiien loan opiolddependent popubiton.
`was recogntred as an opioid agonist. whereas when admtnlslo
`intrarnosoularhr. combinations oi
`buprenorphinethth naloxone produced opioid antagoniotaclions similar to nnloaone. in methadone
`mauit'Iiined patents and heroinIdepcndc-nt subrwts. tntiaienous adrnirrrsbaiion ot buprenorphinetnaioicone
`GDtlItilt‘ialtUI'E procrpttaieci opioid intlidrawd and has perceived as unpieasanland dysphcirtc In morphine-
`stabtinad subiects. nitrayerioushr admetrsiered corribtratrons oi buprenorphine W'ili'i naiprrone produwd
`opioid arsagonisl and Withdraw etlects deli-rem ratio-dependent the most silence muidrawai attracts
`were produced by ztIand 4:1 ratios. less lntenseby an 3:1 ratio. SUBDXONE tablets contain buprenorphine
`with naioirone at a ratio ol 4:1.
`
`Phamracokinetlm:
`_
`Absorption.
`read hine increased with lira 5an cat dose of SUBUTEX and SU BUXUNE. and
`Fbsma tenets of in
`plasma levels at n II aorta ncrcased with the suIbtl
`uai use at EU BOXONE (table 1}. Titan: was a Wide
`It'lilIti-liittitil'li varrabrtioriri the sobit
`labsorption o buprenorphine and naiorronc. but Witilil'i subjects the
`ionabtl'rty unis low. Both
`and
`[1 at it
`renorphine increased in a linear iastiton torrid; the increase in
`dose (in the range at it to
`me). although
`a increase tires not atrocity dose-proporironat
`Naioxone did not aliect the pharmacotrinetics at on morphine and both SUBUTEX and EU EUXONE deliver
`similar
`iasnta concentrations at buprenorphine.
`e iairetsoi naioirone were too low reassess dosa- I
`prraio onairty. At the three microns doses of 1 mo. 2 mg. and 4 m%_leriatsabove rite line at
`retaliation
`{0. 5 normLa were not detected beyond 2 hours in seven at eight so pacts. In one Individual. at
`In time
`dose. the his measurable concentration was at 8 hours. li’t’tthln each sublect {or most oi the subjects}.
`across the doses there has a trend toward an increase in naioirone concentra one with Income in dose.
`Mean peak naloirorto heats ranged irom 0.11 to 023an in the dose range ot1~rt mg.
`
`Tablet. Phannacokinetic parameterw buprenorphine alter the administration of 4 mg. limp, and 16 mg
`Suboxone° doses and 16mg Subut
`dose (mean (%GV)).
`Pharmacoklnettc
`Suboxone'
`Suboxone'
`Suhoxone'
`
`Pun-meter
`4 mg
`8 mg
`16 mg
`Cunning/"1L
`1.84 (39)
`mm)
`5.95 (as)
`547 (23)
`
`
`AUCHI.
`l2.52 (35)
`20.22 (4])
`I 34.89 (33)
`32.63 (25)
`hour. ng/mL
`Distribution:
`Buprenorphine is approximately 96% protein bound. prirnarity to alpha and hem globulin.
`
`Naioxone is approximately 45% protein bound. primarily to albumin.
`Metabolism:
`Bupreno
`ine undo cos both N-deatrytation to norbuprenorphine and giucuronidatiIon. The Ndeaikytation
`athway s mediated
`cytochrome P-450 3A4 isozyme. Norbuprenorphine. an active metabolite. can
`rther undergo glucumnidation.
`Natoxone undergoes direct glucuronidatlon to naioxone S-glucuronide as well as N-dealkylation. and reduction
`oi the Bow group.
`Elimination:
`It mass balance study at buprenoi hlne showed corn tote recovery at radiotabat in urine repeat and [does
`{69% collated up to 11 days alter
`$.Atmostait of
`titanium aoorruntod iorrn terms oibinarenoichina.
`nod] prenorphinu. and two untdanrifi
`buprenorphine metaboldes. In urine. most at bupreno line and
`norbuprenonpahinenae maltreated (bupreno lilne. 1% imam 9.4% mortified; nortiupren
`me. 21%
`tree and it o co u‘gatedt. In tacos. almost a | oi the buprenorphine and no
`protorphlne were tree
`(tiuprenorpiitnti. ‘
`it: tree and 5% contrasted: norbupronmpiitne. 21 “fa tree and 2% coniugated).
`
`Page 1
`
`

`

`
`
`
`
`Buprenorphine has a mean elimination half-life irom plasma of 37 h.
`Naloxone has a mean elimination half-life from plasnra of 1.1 h.
`
`_
`_
`I
`I
`the client of hepatic lrnpnrnnont on the plinrrrracoktnetlcs ot buprenorplnno and nahxone is tintirrrimr.
`Since both drugs are extensively nIrelahollzed. the plasma levels will he expected to be lrrphcr ill patients
`with moderate and severe hepatic irripainrteIrit. However. It is not known whether both did 5 are affected
`to the same degree. Thoroiore. in patients with he
`do tIrn pairrnentrlosape slioutd be adios ed and patients
`should be observed for wmptoms or proctpr
`opioid withdrawal.
`
`.
`.
`No differences in buprenorphine pharmacokinelics were observed between 9 dialysrs-dependent and 8
`normal patients following intravenous administration of 0.3m buprenorphine.
`The sheets of renal failure on naloxone phamtacokinetics are unknown.
`
`din interactions:
`of ketoconazote {ion m day). a
`Ct’ 3A4 noihnorsandlnducersm oharrnacoldnellc interaction sin
`potent lnltlbrtoroi CYF BM. in 12 patients stabilized on SUBOXONE Bing (n213dr12rnIg {Pb—5 or 18mg
`hull 1 resulted ln increases in boprenorphlna mean C
`values59mm it.
`to 9.
`.5.I.’i to rt.-t_and 9.0 to
`?.t and mean illit‘.values [from 30.9 to415.9. 41 .9 to§2 and
`.3 to 120) respectrvclyfiubocls mustang
`or SUBDXDNE should be closely monitored and
`require dose-reduction rirnh tutors of
`and such as aaole antrtonpai agents (so. kctoconaaoto). macro do HlltllJlDlJL‘b’ (no, eryttrromyctir) and HIV
`protease inhibitors ten. ntoravir incfirravtrand saquirrawrlars ctr—administered. The interaction at trrrpreriorphure
`witir GYP 3M inducers has nol been rnvestrnated: therefore it is recommended dial pcuents receiving
`SUBUTEX or SUBOXONE should be closely monitored it inducers of CYP and (on. phenobarbital.
`carbomareplrte. ohonytoln. nfairtprctnl are tin—administered {SEE Wr'iRNlNGSl.
`
`.
`I
`I
`aodetflmy oi SUItiOXDNE and SUBUTB<aredenyed from studies of buprenorphrne
`sobtrrrprial tabletj'onrru irons with and undrool naloiiorIie. and from studies of sublrnguai administration
`of a more bloavarteble odtanolrc solution at unprenorphrne.
`
`SUBOXONE tablets tcve been stodled in 5?5 patients. SUBUTEX tablets in 1534 patterns arrdtruppororphine
`subtotpoal solutions to 24rd patients. i'ttolat of 12m torrralos have received hoprooorphrne to ethical tnais.
`Dosrn recommendations are based on data from one trial at both tablet formulations and two trials of the
`edition in solution. All trials used bupranorpttlirri in coniu nation with
`to assess the
`hosocral mam as part of a
`comprehensive addiction trsaorrerrt program. There have been no r: roost studies oon
`efficacy of buprenorphine as the only component citreatment
`
`Ls were randorrrly motored
`.325 tteroln-odtl'rded so
`to attribute otinnghoebo and active controlled etc
`per dayor
`lacebc tab is. For subjects randonnired
`to editor SUBDX E 15 in per day. 16 m SUB
`to eittraraot'nie treatment using began wt
`one B mg tablet of SI BUTEXon [la 1. {allowed by 16 Into
`Enroll mg IaIblctIsloiSUEUTBon Day 2. On Day 3. tiioso [EDDDII'l'iDZEd to rerieirc
`XDNEweresnrii: red
`o the combination tablet Subjects randomead to
`coho recanted one lnoibo taIblIot on Do i and two
`taceho tablets perday ttrorea terfor tour wants ubiects were seen dar
`in the clinic (Mon
`y throuplr
`Eriday} iordosrnaand eithacyassessments.Take-homodogswore crowded loIrweetrends.SUIJJECISwere
`the eradication under the tongue toflpmximatehzfi to 10Irriinutes onul com Isiah I
`dissolved. Subjectsremivedonehooroi lndnirdual cou ’
`rnoéierwee ands s
`recession of it
`edumtron.
`The pnrnary study comparison ms to assess the efficacy 0 UEUTEX aIr-rd 5U DXDNE individually against
`placebo. The percentage of tlirioe-weekh unnesain
`‘ that wine nérfiutrve for non-study opiords was
`stathitlwtty higherlor both SUDUl'EX and SUBDXU E. than for tile
`.
`
`in a double-hind. ttoubteduminy._paratlel«proup study comparing liuorenorplttne edraitolit: solution to a
`toll anonist active cordrol 162 suhyeclsteor randomized to receive the ouranotrc sublingual solution of
`he retro hint: at 8 heyday a dose which is reophly comparable to a dose at 12 inoiday ot SUBUTEX or
`E). or two rota .
`low doses of active control. one of winch was low enough to serve as an
`alternativoto placebo dunnoa 3-10 day tridtictron phase. a 15-week maintenance phase and ti tweet:
`detriiriflmtron phase. liuprenorptitne was titrated to maintenance dose hy Day 3; active control doses were
`titrated more gradually.
`
`red by approximately 20-
`Mainteronoe dosing continued tltrou hWeek 17. and then medications were la
`3tl% perwseli river Weeks 18-24. wr
`placebo dostng for the last two weeks. ubrects received indrvrdual
`andror group counseling weekly.
`
`oi thriceoveetdy urine samples [legalivetor non-stridy
`based on retention in treatment and the perconta
`opioids. biipreoorphlrio was more ctfectrye than IroIiow dose of the control. Il‘l ttoeprnp heroin addicts in
`treatment and in roduorno distress of oprords while in treatment. The effectiveness of buprerrorptiine. ti nip
`per daywas similar to that of the moderate acute control done. but equivalence was not tiernonstnrled.
`lo a doseoonltoliod.dottble-hlit1d, parallel
`Iroup. its-week study. 73f sobicctswore randomized to receive
`one of tour doses at buprenorptrine ethane c solution. tin renorplrtrte was dilated to mnntcnltnce doses
`over 1-4 days [tattle 2t and continued tor t 6 WBEJTS. Selim received atltaisl one session of nlDS otucruon
`and additional ooonsefirrp ranging from one hour per month to one hour permek. depending on site.
`
`
`
`3352. Doses ofSubllngual Euprenorphlne Solution used forlnduotlon In a Double-Blind Dose Ranging
`Induction Do“ Maintenance
`
`Da Da Da
`dose
`2y
`3y
`i m
`_
`l m_
`l in
`m.
`_
`_
`4 III.
`
`
`at solinlon. Doses it this table cannot timid; be delivered in tablet form, bid for comparison purposes:
`2 mo so Litton would be roughly equtwrterrt Ina mo irrtdrn
`4 mo solution would be roughly equivalent rod mp table
`8 mg solution would be roughly equnclont to 12 mp tablet
`16 mo sotutbn would be roughly euulvotuntlo 2‘4 iitp tablet
`
`Based on retention in lrmbnont and the percenltipe of thrice-weekly urine samples negative for non-study
`optoids. the liner: tripltosl tested doses were superior to tho 1 mg dose. Therefore. this study showed that
`renorphlne doses may lie attractive. The 1mg dose of buprenorphrneIsubtrnguat solution can
`lie wrestlers lobe somowtoit 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 mp.
`INthtATlUNS AND USAGE
`SUBOXONE and SUBUTEX are indicated for the treatment of opioid dependence.
`DDtitRthDIDATlDNS
`SUEDXDNEonId SUBUTEX should riot be administered to infinite who have been shown to be hypersensitive
`to buprenorphina. arid SUBOXONE should not be administered to patients who have been shown to be
`tiypursonsltrrc to neloitorie.
`WhflNlNDS
`.
`I
`hespiraforytio tension:
`Slprntrcant resp ratory depression has been associated with IIrupronorphine. partlculoity by the intravenous
`rooteJt number of deaths halo occurred when nothcts have rntravcrroosly misused buprenorplriire, usually
`with Iberraodraeeprnas concomrtan . Deaths have also been repodod rn association mth conrntnrrtant
`administration ol bu rsno time no tether depressantssuch as alcohol or othercploids. Patients should
`he wanted at the po called
`it
`rot the sclf~admlnistration oi beneddrazepines or other depressantswhite
`under treatment with SUDUT
`or SUBOXONE
`IN THE [FREE OF OVEHDUSE THE FRIMi‘tRY MANAGEMENT SHOULD BE THE RE-ESTi'tBLlSlIMENT BF
`ADEDUi‘tTE VENTILATlDN Will-i MECHANICALASSISTANCE 0F RESPlRATlDN. IF REDUiRED. Ni'tlflXDNE
`MAY NDT BE EFFECTIVE IN REVERSlNG ANY RESPIRATORY DEPRESSION PRODUCED BY
`BLiPFlENDFlPHINE
`
`lienls with compromised respiratory function
`Sti HDXDNE and SUEDTEX should be oeedwidi notion in
`Lop. chronic obstructive pulmona
`disease. cor pulmorra e. decreased respiratory reserve. hypoxia.
`ypercapnla. or preerdstlnp respll'd or depression).
`L'i'io‘ti'epmssien:
`Pauenls receiving buprcnorphtne in the presence of odierI narcotic analoeshs. enerd anesthetics.
`DEttZDtlIEZEpIiBS. phenuiiirazines. other tranqurtee's- sedatrvafhypnotics orother NS depressants (irrcludtno
`alcohol may exhibit increased Otis de resslort when such combined therapy is contemplated. reduction
`oi the use of one or both agents shou be considered.
`Dependenw:
`ndenoe
`Bupreno
`the ice partial appristatthe mu-ooiate niceptnranrt dirort'rc administration produces
`oi the opiqtild typo, characterized withdrawal upon abrupt deroontinuati'on or rapid taper. medmidmml
`syndrome h milder than seen in ifull concrete. and pray be delayed to onset
`Hepatitis. fie
`in: orients:
`.
`_
`them of
`infill: hepatitis and hepatitis with hundred have been observed in the addict popuhtipn recehr'np
`bu
`no both or cliniaillrhtsarrdlnpost—rnaiitebnpadeseetcnt iepoitsThespectrumolahnomrslm
`ranges from baiislentawmptomatic eliiiretiorts in hepatic transamtnases to case reports of hepatic letters.
`he I
`necrosis. hepatorenal syndronre._and lIiepatro once trolopathy to marry Loses. the presence of pre—
`o stirro tiverc
`a obnonnaliuos. infection wrthhepefilis
`orhepctrtts C virus. torrcomiItanl usane otouror
`potential”?!I hepa toiecdrops. and popular: injecting drop use may have plated a causative or conurbutoI
`role. In
`crimes. Footflomldatawere aidhbletodetennure treetr
`ttreabnonrrritity.ihepossltiil y
`crests that buprennrplirnl had a Inactive orIcontnbulory retain the d
`pmenl ot the hepatic abnormality
`in some cased Measurements oi IIrveIrfuncuon tests prior to imitation of treatment is recommended to
`estathsti a cocaine. Eeriodlc mondonnp of liver tonclton tests durinp treatment is also recommended. it
`biological and all
`real evaluation is recommended when it h
`tic event lswspected, Depondr
`on the
`case. the d _
`sho _ he caroiuih discontinued to pro-vent with niwrrt symptoms and a return loll cit dnip
`use. and s
`monitoring of the patient should be initiated.
`
`.
`_
`_
`_
`_
`_
`Allergic Restroom
`poses planets and chronic Itnrpersensitrvihr to huproncrphrnc have been reported both in clinical tools and
`iii the postmartretrnp 2
`hence. The most common signsand symEtIiIoIrne include rashes. hives. and
`Riontus. Cases cl hrII
`ospasrn. anpicnourotic edema. andIanaohzI
`lc shoctr have been reportoct n
`rsiory oi hmorocnsitrw‘ty to trqurenorphlno is a Ioorrtratndlutron 0 corner: orSuborano use. it history
`oi lTyDBiEEI'lSI‘lNfl)’ to rraloxone s a contraindrratioir to Suboxone use.
`Dorrie Airioriieic Patients:
`I
`SUBOXONE and UBUTEXI
`impair the mental or physical abilities required for the performance ofI
`poterrttaih cancerous looks so
`as driving a carer counting machinery. especially dIurtno dnig induction
`and doseIadrostrnenL Patients should be captioned a cut operatir
`ferocious machinery. trichdr'no
`automobiles. until they are reasonahly oonarn dtathupren
`rtne rein
`does not adversely affect their .
`ability to airplane in such mops. Litre other oproids. SUBD ONE and
`BUTEX may produce orthostatic
`Irypotenston In ambulatory pouches.
`tread in it
`endlocreased nonmetal Framers:
`SUBDX ill and SUDUTEX. like other potent oploids. may elevate cerebrosplnal fluid pressure and should
`be used vnttr motion in padmlswiur head mllllli'l intracranht lesions and OIhEI' circumstances where
`ceretriosptnal pressure may be Increase]. S
`XDNIE and SUBUTEX can produce rniosls and changes in
`the level at consciousness that may interfere with patient Limitation.
`
`.
`Opioid widrdmwof effects:
`to produce matted and Intense withdrawal
`Because It contains naiorrone. SUDDXDNEls Illnhg like
`symptoms rt misused parenterallo)
`rmlrindoals
`oenI m on 0 lord aponlste such as herein. morphine.
`or methadone Sublrnptroity. SUD
`NE may cause croold with rowel symptoms in such persons it
`administered before the aponlat clients of the opioid have subsided.
`
`opera :
`ERECAIIITIONS
`SilhDXDNEIand SU BU‘l‘EX should be administered with caution in elderly or debilitated patients and those
`with severe err
`lrrnent ct hgialic. pItitnrona
`. or renal function; myiredema or tnpothyroidtsm. adrenal
`domestic
`_
`icy tap. on son's disposerJ
`Sdeprossion oroarna: lord; psydroses: prostatrotrypertroptn
`orurathiat stricture: acute alcoholism; delirium tremons: or kyphosooliosrs.
`
`the affect of hepatic impairment on the pharrnacoklncttcs ol buprsnorphtne and notorious is unknown.
`Since both drops are extensors Irnetahotlzed. the plasma levels will be expected to behrnhor in patients
`with moderate and severe hope
`trnpalm'riint. However. it is not known whether both din
`are attested
`to the some degree. Therefore. dosage should be adru sled and patients should lie watch
`tor symptoms
`of precipitated opioid Withdrawal.
`
`Buprenorphine has been shown to increase intracholedochat
`be administered wrth caubon to patients wrth dysfunction of
`
`ressore. as do other opioids. and thus should
`e biliary tract
`
`As with other mu-oplold receptor agonists, the administration of SUBOXONE or SUBUTEX may oinoIhiIem
`
`Page 2
`
`

`

`the diagnosis or clinical course of patients with acute abdominal conditions.
`I
`Bunrenorphrrro is metabolized to rrorbufirenorpirine by cytochrome CYP 3M. tiemuse tJI‘i'P 3A4 Inhibitors
`may increase plasma ooncerttnttions of uprenoruirine. patients already on (NP and inhibitors such as ozole
`aiihirtngaistpn. Irotoconazolo}. macrolirie antibiotics up. orghromIfi'n). and tilt!
`rotuaso Inhibitors {c.g.
`rrtorravir. in iriovli and saouinoetij should have their use oi UHU . or SUBDX NE adjusted.
`
`Hostel on anwiotal reports. titers they been interaction between buprerrorphinrrand bamodiaieIpines. There
`have been a number of reports In the post-mediating expo hence a puma and death assnoate with the
`concomitant intravenous misuse of btrprenorphine and Immediate has by addicts. In man of Liner: cases.
`buprenorphlrrrr nos misused
`self-Ingestion of wished SUBU
`tablets. 5U BUiEX an SUBUXONE
`should be prescribed wtlh cant on Inpatients on benaodrazopirtes or other drugs thatIact on the central
`nervous system. regardless of whether these drugs are tattoo on the adieu: of a physrcian or are taken as
`drum of a use; PatinriIm should be named of the
`lenlial darn eroi the intravenous sell-administration
`of benrodrazeptrres while under treatment With 3 EDXONE or
`1J8 UTEX.
`Informaflarr for Patients:
`Patients should Intonii their family members that. in the event of emergency. the treating physician or
`emerpon IroorIt'r stall should be informed that the
`dent Is physmlly dependent on narcotics and that
`the pollen IS being treated with SUBOXDNE or SLI UTE):
`
`Patients should be cautioned that a serious overdose and deathImay occur if benzodiazepines. sedatives.
`tranquilizers. antidepressants, or alcohol are taken at the same time as SUBOXONE or SUBUTEX.
`
`SIJBOXONEand SUBUTEX m tmpairthe mental or physical abllifles required [or the pcrlorinahoe oi
`potentially dangerous tasks sun 1 as dmrrnn a '1' or oggItIaIan machinery, especially dunno drop induction
`and doseIadirrstrnent. Patienlsslinuld be cautioned a
`toperaurIfl hazardous machinery. Inclurfinp
`aulprirobiles. until they are reasonably cenain tiiat bupreno
`me
`are
`does not adversely oilecl
`Iirrir .
`abltrtyto organs In such activities. Litre otltoroploids. SUBU ONE and
`BUTEX may produce orthostatio
`hypritenslon in ambulatory palirm u.
`
`Patients should consult titelr physician iiother prescription medications are currently being used or are
`prescribed for future use.
`
`I
`_
`_
`.
`Carcinogenesis Metapenesis amino oi'rmenio! Fer-time
`'
`entities or bupreriorphiiie
`ionooenici’pr data on UEDXDNE arenotavatblile Ba
`ue-Daw rats and CD4 mice. Bupreriomhlrie was adirenistered in the dlotto rats
`at doses of 0.5. 5.5. an 56 mar day fesli'mated exposure wowgoximat
`Elsi. 3 and 35Itirmis the
`recommended hurrian daily so irrpuat dose of to m'llam a root
`sis) for i months. Statispocrtty
`Significant dose-related monstrous in testicular ir'iIiorsti
`I [Leydig‘sl cell tumors occurred. according to the
`trend lost aoiiistert for siiorimi. Pair—ruse comparison oftliii high dose against metro! failed to show statistical
`Significance. In an 85ml: study In {JD-"I mica. buprenomhioo was not mminonenic at rhetary doses up
`day {wheeled opiosure um approidmetehrBtilimes lite roaommendod lirmnn daily sublingual
`dose of 1 mg on a motor? beers].
`
`enic in a bacterial mutation
`SUEgg’DNIg‘iho rt:i combinadonof buprenorphineIand natoxonewas not in
`assay (Panes tesrlusern four strains of S. nipirimunum and two strains of EI co . The combinabon has not
`IciaIIstopeEro In an in irrim mopenetrcassay in human iymphowtes, or in an intravenous micronucteus test
`SUBUTEX: Eupreoorptr‘ineuos studied in aserios of tests utilizing gone. chromosome. and Didi interacbrxrs
`in both proitaryotic and euka olic systems. Results were riepatrve in
`. t {Saccitarornyces oererrsocy
`for recombinant. gene contra
`ntI or torward mutations: nooatrve to
`cities subtitle ”'roo assay. nepapue
`torclastopenrorty in 0H0 cells. Ch nose hamster bone marrowIand
`erma
`rea cells. and penance I|'|
`the mouse lymphoma L51 rev assa ,Fiesultswore
`normal in the has tea 'rtepauve in shidirrs in two
`Laboratones. but DDSillVb iorirame
`Ift mutation ate _rph dose Smpi'plarolIiriI a third slu
`. Results were
`sieve In the Green-Tweets (E ooiilsurynoi lest. positive In a D
`syntheses inhibition {
`I) test verb
`sticutartissue from truceI for both in Mind inIvriro incorporation of [itlld‘iyinlome and posruvo in
`unscheduled DNh symlhests [U DE) lest usanp testicular cells from mine.
`I
`horror otirtrirhe
`I
`renter tequnralent
`or or
`administraoon oi SUBOittUNE In the ratatdosetovois oi 500
`recommended
`titties
`in
`day or
`rerrtenestehated exposurewasa Medley
`an Impact use oft mp one or m? basis produoe a reduction In fertility demonstrated
`by reduced emaileooiiceptxrn cries. ii dietary
`a nil
`ppnré
`ulvrderrt to approximate
`it) deay'.
`surowas approximately 5 hmes trio recommen
`human daily subllnoun rinse it 1 my
`slsl had no adverse effect on fertility.
`
`SUBUTEX: Reproduction studies at humanogtttne In rats demonstrated no evidence of impaired fertilit
`at daily oral doses up to burned: day iestrrn ed exposure was
`iorrrnialetyISEi times the recommen or]
`human daily sublirtiiurtIl dose of 1 mp one n
`basis or up to ntghpiday enorsr: (estimated exposure
`was approximately 3 times the recommende human arty subirnguai dose at 13 mg on a myrrh?i pasts).
`
`Pragmncy thgory C:
`
`_
`.
`SUBD ONE: Effects on ornb
`-teral development were stutfied in Spraguottawiey rats and Russian white
`rabbflinoltovnnp oral 1:1} an intramuswlar 32) administration at ruptures oiboprenorpltlno anrl naioxone.
`FoIlloIIvfitIrIIIin oratdaIinIrIningIIIuIEIaIItIijon to raw rah his. impratunurilo effects triers obIgIeInIingIaIt UUSOSIIIJ
`toIZ'Jti
`.rae
`or; me
`exposurewasapproierna
`mes on
`I_rrias.
`respectively lira recommecfid hurrran
`i
`subiinouei dose of him on a mip‘rn'fi basis). Nu definitive
`drug-rotated tetatnuenro about: were observed in His and rabbits at iitlranItuscuiardoees up to Hit mp‘mtday
`{estimated exposure was approximately 20 times and 35 times. roIspoctwei . the recorrtrrtrrriueu human
`daily dose ol 8 mp on a mgr‘nii‘ bests}. hoephalus was observed in one or bit fetus irorri the tow-dose
`group and ompharxdo was observed in two rabbit fetuses from the same litter InId'to midoose group.- no
`ndlltgs were observed in fetuses from the high-dose uroup. Potter-i1in; oral administration to the rat. dose-
`rotate postgrmp‘antottm losses. evidenced by increases in the numbers of ca
`resorpuorrs vain consequent
`reductions lit the numbers of fetuses. were obsenod at doses of it} mph/rip! ay or greater (estimated
`roxirrratuiy 5 times the recordmended human daily su Iinliiua dose ul16 mg ona rriry‘ni?
`it: inoreased post-rm Iontauon losses occurred titan oral use of ‘if) motley ay. l-oilowrnp
`Intramuscular administration in the
`and the rabbit. post-implantation losses. as endowed try decreases
`in live feeisesarid Increases in rosoipuons. oocu rted at 30 mgdtpiday
`
`SUBUTEX: Buprenorphirie was not teratoponir: in rats or rabbits alter tin or scrtosos up In 5 monotony
`(estimated eicioeurerttas
`truiomatety 3 and 5 times. respective
`the recommended human any subiinoual
`dose of 16 mg on a moi
`'-
`sis). after ivdoses up to 0.8 or
`{estimated exposure was approximately
`
`
`
`[1.5 pines and equal to, respectively;1 Lno reconiri-Iioniiorl human oathsublinguat dose of 1 E rn on a ittui’rrtf
`bass}. oratteroraldoses upto Ib mpiliryduyin rats{esbmalcdexposureunisap mxinoteEIPifi times
`the recommended human daily sIublrn as does of 16 top on a or
`in2 basis] and £5 motley try iii rabbits
`it‘stlnrated exposure was ap promote 30 times the recontmen ed Iiurnan oath sublhignal dose at 16
`me on am 2 basis . sipni mnt imam in skeletal ainormanties tap. more thoracic vertebra or thermo-
`lumbar ribs were no
`In rats ailnr scadrninistration pi i
`rude and up {estimated exposurewas
`approximately 0.6 lJITlibS the recommended human ear
`srrbiinpual use of to mg on a mom? basis). but
`were not Iobsorved at oral doses on 19160 nrpikp‘dey. iioreases in skeletal abnonnafities in rabbits it for
`en odnunIrstrabon ol Sdeay [esunateo exposure was appnixlrnatehi E u'mos the recommended human
`daily sublrnnual dose or to mg on a m in2 Less) ororai aibninlsrnilion or 1 meat/day or water {orientated
`exposure was approxirInately equal to
`a recommended human daily subliriptnl use of 1 mg on a myrrh?
`basis} were not statistically significant
`in rabbits. buprenorphlno produced statisltrally significant pro‘lmpiantation losses ntor‘al doses of 1
`rriuiiriy'day orproaterarrripost-lmpiantatlon losses the! were statistically significant at process of 0.2
`mIEIi‘lipr'dugy orgreator iostrrrrated exposure was approximately 0.3 times the recommended human rlaily
`5
`Into
`dose ol16 mg on a mptrrfi basis}.
`There are no ade uate and well-controlled studiesIof SUBOXONE or SUBUTEX in pregnant women.
`ns
`0
`e e
`s.
`SUkBI0)I(ItIJNIEIrIiIr S BU EX should onty be used during pregnancy if the potential benefit iustifies the potential
`
`5 we? r
`h'
`'lhb
`istreated i
`firepower-"grasps.
`r
`‘mad 3
`times
`rn
`a min
`u renorp iriu
`mwr
`ocrawasrro
`inproprian ra
`the recommended human daily subiinpuat dose oi 1 ii gap one mnirril beets). orhllgttility andiryaod- and
`postnatal devolraprnent studies with lmprenorphirto In rats Indicated Increases In neonatal moriall
`after
`oral dusts pl 11 Mold? and up ianproxrmatoly 0.5 times the recommended hurrah daily sub 'ripual
`dose of iiiflnaia Ion a mo]
`hosts). a tor rnrdoses of 0.5 moho’dayand up (a
`roxi'ntatelybd times the
`rticximrrre
`Iiurrrandat subhipualdoseofifinroonamg’nfibasls) and
`erscdosesolllt m
`and upIII: proramateiy ti.
`omits the recommended human dairy subtlnpuat dose of to rep on a
`rrt2
`basis}.
`in the oomtrrenre of manure; reflex and startle response were rtoted In rat ups at an ora dose
`in
`is.
`351??
`I
`(approxrmatety 50 ruins the recommended human dairysubtlnouai use oi 1 b mg on a
`Neonatal Withdrawal:
`Neonatal withdrawal has been reported in the infants of women treated w'dh SUEUTEX during pregnancy.
`From postmarketinp reports. the time to diesel of neonatal wrthd rawal symptoms ranged from Day 1 to
`D
`riot life with mostoouimnp on Day 1 . Adverse events assocoted with neonatal withdrawal syndrome
`the dried hypeitonla. neonatal tremor. monatal agitation. and myoclonus. There have been rare reports of
`convutstons and In one case. apnea and bradycardra were also reported.
`
`Nursing Mothers:
`uction strides