`
`AMN1023
`IPR of Patent No. 7,919,499
`
`

`

`53
`1999
`
`EDITION
`
`PHYSCANS'
`DESK
`REFERENCE®
`
`Medical Consultant
`Ronald Arky, MD, Charles S. Davidson Professor of Medicine and Master, Francis Weld Peabody Society, Harvard. Medical School
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`• • may be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical, photocopying, record-
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`ISBN: 1-56363-288·8
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`® Printed ~n recycled paper
`
`AMN1023
`IPR of Patent No. 7,919,499
`
`

`

`ommended ¢at the product be stored at room temperature
`(25"C);' hqwe\rer, brief exposure up to 40"C does not ad-
`versely affe.c:t the product.
`·
`Caution: Federal (USA) law prohibits dispensing· without
`prescriptiop.
`.
`Distnbuted by:
`DuPont Pharma
`Wilmington, Delaw~e 19880
`Manufactured by:
`. ..
`.
`McGaw, Inc. __
`Irvine, ·cA. USA 926it!-5895
`6270-3/Rev. November,' 1997
`PENTASPAN®_and HESPAN® are registered
`trademarks of
`Tl-J,e DuPopt Merck Pharmaceutical Co.
`
`REVIA® ·
`[reh "vee 'uh "]
`(naltrexone hydrochloride tablets)
`
`DESCRIPTION:
`REVIA (naltrexone hydrochloride), an opi<iid a:D.tagonist, is a
`synthetic congener of <ixymorphon~ with no opioid agonist
`properties. Naltrexone differs· in structure from· oxymor-
`phone in· that the inethyl group on the nitrogen atom is re-
`placed'by a cyclopropylrilethyl group. REVIA is also related to
`the pi;> tent· opioid aritagorust, naloxone, ·or n-allyl.noroxymor-
`phorie [NARCAN® (nhloxone hydrochloride)].
`
`:~:- .. ·.
`
`\
`
`.
`
`_OH ._,H-
`~-
`
`936/DUPONT PHARMA
`PHYSICIANS' DESK REFERENCE®
`----------------------------------------~----- ------------------------------------r-----------------------------------------
`Pentaspan-Cont.
`5 to 40%. The activity of naltrexone is believed to be due to
`There are no. data that demonstrate !IJl unequivocally ben-
`both parent and the 6-(3-naltrexol metabolite. Both parent
`eficial effect of REVIA on rates of recidivism among detoxi-
`drug and metabolites are excreted primarily by the kidney
`fied, formerly_opioid-dependent individuals who self-admin-
`(53% to 79% of the dose), however, urinary excretion of un-
`ist!ir the drug. The failure of the drug in this setting ap-
`changed naltrexone accounts for less than 2% of an oral
`pears: to be due to .poor:m!)dication compliance.
`dose and fe(!al excretion is a minor elimination pathway.-
`The d,rug if?. reported to be of greatest use in good prognosis
`opioid addicts who· take the drug as part of a comprehensive
`The mean elimination half-life (T-1/2) values for naltrexone
`occu11ational _rel;labilitative program, behaviori:U contract, or
`and 6-(3-naltrexol are 4 hours and 13 hours;. respectively.
`Naltrexone and 6-(3-naltrexol are dose proportional in terms
`other compliance-enhancing protocol. REVIA, unlike metha-
`of AUC and Cmax over-the range _of 50 't9 200. mg and do not
`done or LAAM Oevo-alpha-acetylmethadol), does not rein-
`force medication compliance _and is expected to have· ather-
`a,cc;umulate. after 100 mg daily .doses, . :, .
`A!Jsorption .
`.
`. _ .
`.
`apeutic effect only when given·l,l.Ild!)r ext_ernal -conditiqns
`Follov.ri_ng oral !idministra,tion,. naltrex0ne undergoes ra,pid
`that support continued use of the medication. -
`·
`and nearly complete absorption with approximately 9{1% of
`..
`..
`.
`Individualization of Dosage:
`the dose absorbed from the gastrointestinal tract. Peak
`DO NOT ATTEMPT TREA,TMEN'l'_ WITH ilEVJA 1JNLESS,
`plasma leveifi of both naltrexone and 6-(3-naltrexol occur
`IN THE MEDICAL JUDGEMENT OF THE PRESCRIBING
`Within dne·hour of dosing.
`·
`PHYSICIAN, THERE IS NO REASONABLE POSSIBILITY
`Distribution
`·
`·
`.
`OF OPIOID USE WITHIN THE -PAST .7-10 -DAYs-.. IF
`THERE' IS ANY QUESTION OF OCCl]LT OI>IOID DE-
`The volume of distribution for naltrexcirie folloWing. intrave-
`PENDENCE, PERFORM A NARCAN _CHALLENGE; TEST.
`nous administration is estimated-to be 1350 liters. In vitro
`Tre_atnwnt of·A!coholisin: .
`. .
`. _.
`tests wi.t~ human plasma show naltrexone ~o be 21% bound
`The · placebo-controlled studies that deqi_(mstr~tecj. the effi-
`to_plasma proteins over the therapeutic dose range.
`. cacy ofilEVIA as an. adjunctive treatment of alcoholism used
`IV)etabolisl'!l
`- L •
`a dose regimen of REVIA (naltrexone hydrochloride) 50 mg
`The systemic clearance (after intravenous administration)
`once daily for _up to 12 weeks. Other dose regimens or dura-
`ofnaltrexone is "-'3.5 IJmin, which exceeds liver-blood flow
`. _ -'.
`tions of therapy were not studied in these trials, :·
`(rvl.2 IJmin). This suggests both that naltrexone is a highly
`Physicians are advised that 5-15% of patients taking REVIA
`extracted drug (>98% metaboliz~d) and that extra-hepatic
`for alcoholism will complain of non-specific side e_ffects,
`sites of diug metabolism exist. The major metabolite ofnal-
`chiefly gastroii::ttestinal· upset. Prescribing physicians have
`trexone is 6-13-naltrexol. Two o~her minor metabolites are
`tried using an' initial 25 nig dose, splitting the daily dose,
`2-hydroxy-3-methoxy-6-13-naltrexol and 2~hydrojcy-3-meth­
`and adjusting the tiine of dosing with liniit!ld.success·: No
`yl-rialtrexol).e. N,altrexone and its metabolites are also con-
`do:;;e- or pattern' of dosing has been· sho\vn to be 'Ii:wre effec-
`jugated to form additional metabolic products.
`tive. than any other in ;reduclligthese complaints for all pa-
`Elirttination
`·
`·· ·
`tients.
`·
`The ·reriai cl~arance for naltrexone ranges from 30-127 miJ
`Treatment of Opioid Dependence:
`IQ.in and suggests that renal 'elimination is primarily by glo-
`Once the patien.t has beeh started on REVIAl 50 mg once. a
`merUlar -filtration. In comparison, the renal clearance for
`6-13°nhltrexol ranges from 230~369' illmm, suggesting an:
`day will produce adequate clinical blockade· of the actions of
`parenterally administered opioids. As with many non-ago-
`additional renal_ .tubular secretory mechanism. The urinary
`nist treatments for adc:fiHioii, REVIA is of proven value only
`excretion of unchange~ tuil~r!)xone accounts__for less thilri
`when given as part of a compreP,ensive plan of management
`2% of an oral dose; tirimiry excretion of unchanged and con:
`jugated6-(3-nalti-e~o(accouht's for '43% of aii. oral dose; The
`that indude_s some measure to ensUre the patient takes the
`medication.
`·
`pharmac~kirl~ti~ profile ofnaltrexone s_uggests'th'at naitrex-
`A flexiole approach to a dosing tegimen may 'be employed to
`one and its metabolites may undergo ent'~rohepatic ':recy-
`enhance compliimce.Thus, patients' may receive 50 mg of
`cling.
`·
`·.
`·
`·
`REViA 'every we!)kday 'With a '100 mg dose on Saturday or
`Hepatic and Renal Impairment
`patients niay receive 100 mg every other day, or 150 mg ev-
`Naltrexime appears to have extra-hepatic sites of di-ug me-
`ery third day. Several of the cliriical studies reported in the
`tabolism and its major metabolite· undergo-es active tubular
`literatUre bave employed the following dosi.il.g regimen: 100
`secretion (see Metabolism above). Adequate studies of nal-
`mg on Monday, 100 mg on Wednesday, and 150 mg on Fri-
`trexone in patients with ·severe hepatic or renal impairment
`day. This dosing schedule appea±ed to be acceptable to
`have not been· con-ducted (see ·-·PR.ECAUTIONS: Special
`many RE:VIA patients successfUlly mai.D.taining their opioid-
`Risk Patients).
`·
`' ',
`. .
`free state.'
`chnii:al Trials:
`Experi!)rice with.the supervised ·ad.J:irinistration of a number
`Alcoholism:
`of potenti'ally hepatotoxic agents suggests that 'supezyised
`The effic,:;icy ofREYIA as ah fiid to the treatment of alcoholism
`adnllnistratiorr and single doses ofREVIA higher than ·so mg
`was tested !n, placebo-.~ontrolled, outpati!!n~, double b,lind
`may ha'v'~- ari ·associated incref;J.sed risk of hepatocelluiar in-
`jury, even thotjgh three-times a: week dosi.D.g has been well
`~rials .. 'fhese studies used a dose of REVIA 50 mg once daily
`for 12 weeks as an adjunct to social and psychotherapeutic
`foJerat_ed lli-'the :a.ddict population' and iii initial ciinical tri-
`methods when given'i.ui.dei conditions tpat !!nhanced pa-
`als in' alcoholism. CliiPc!:! using this approach shoUld bal-
`t(ien,t cqmpliance. Patients with p_sychosis, dementia, ana
`ance the possible risks against the probable benefits and
`secondary psychiatric diagnoses were excluded from these
`may 'wi!!ii to' iilamtain 'a higher 'index' of suspic;ion' for' ClTl.i:g-
`studies.
`·
`·
`·
`' ·
`assodated hepatitis and 'ensilre pati!)nts are _advised of the
`. In one of these studies, 104 alcohol-dependent patierits,were
`. need to report non-specific abdonlin'l:tl complaints (see In~
`randQ.Inized to receive either REVIA 50 mg once 'd~y or 'ji~a,­
`formation for Patients).
`cebo. 'In this study, HEVIA proved superior to placebo :in
`INDiCATIONS ,AND USAGE: -1•
`measures of drinking inclupmg abstention r(ltes (5~% . vs:
`<
`REVIA is indicated: -
`23%), number of drinking days,, and relapse (31 %_-vs. 60%).
`In the treatment of alcohol depen~en~e and for the blockade
`In. a secqnd study.. with 82 alcohol-dependent patients', the
`of the effects of exogeno_usly adininistered opioids.
`group of patients receiving REViA were shown to have lower
`RE VIA has not been shO'\~n-to proVide any therapeutic benefit
`relapse rates-(21% vs. '41%), less alc;ohol--c'rl;lvfng, ~d fe'Ye!
`except as part of an appropriate plan of management for the
`drink.ing days compared with patients 'who' receivE)d'pili-
`addictions.
`cebo, .but .these. results depended on the 'specific a:iialysis
`used. - .. - :-
`.
`- .. '.
`"-'
`., -
`-,. .· .. · ... '
`CONTRAINDICATIONS:
`. 'l'he cfu»cal use of RJj:VIA as adji.mcti,ye pliarm~cqtherapy for
`th~ ~e?-t!Jlent of. ~coholi&m was a1so_ ev~uated. iri a ri!ulti-
`center ~afety study. Thi~ study.of 8!)5 indiyi!fuals with alc;o-
`holjsm i.D.chided patients With comoi:IM :pfiych,ia.'tric i;ondi-
`timis; ·concoml.tant medications, polysubstance abu!:!e. and
`JUV._ disel;l~e. Results or this stp.dy demonstrate~ that the
`s~g~ ef!'ect.'pro,nle o(Jijj:VIAappears tq_.pe ~imilar in .~oth al~
`!!Oholjq _and OP,~oid ~eJ?~nden~ populatio~s, ;ind that s_~Jjo~s
`side ·effects are uncommon. . ' . _
`_
`,
`. ,-
`. In, the clinical studies, treatment' with REVIA supported ab-
`stlnence,_prevented relapse and decreasecfal(!ohpl cons-lu:o,p-
`. tj.on~;In. the ~cqntrglled :itudy, tlie patter.ri8 _of a.bf?ti:o,ence
`and relapse W!)re similar to those observed. in,· the controlled
`studies. REVJA.was nqt uniformly he~pful to' all·pat_ients, B:D.d
`the expected effect of the ,dr.ug is-a modest improv~ment in
`the outcome ofconventionai. tre-atment.
`~ ·
`-
`·
`Tre"'tnie~t Q! Opi~i~ Addi~;tio~; -~ .
`..
`.
`.
`. __ .
`.
`REVIA has :be.en .shpwn to. produc_e 'GQmplete blockade of. the
`euphoric effects of opioids in both volunteer !U}d 9-ddict-
`populations:-When administered· by means that enforce
`compliance, it will prp_duce an eif~ctive, opioid. blogkade, _but
`has not peen shq:wn to, !ltrect the use of cocaine or other :o,on-
`opioid drugs q(abuse._
`: _; , _. ·
`Information will !le s_uperseded by supplements and subsequent editions
`
`•HCI
`naltrexone hydrochloride
`HEVIA is a white,._crystalline compoun,d. The hydrochloride
`salt is soluble in water to tQ.e exte:o,t of abo:ut 100 mg/m.L.
`REVIA is available in scored· film~~;ol:l,ted tablets containing 50
`,
`mg of n!!ltrexone hydrochloride.
`REVIA Tablets !Jlso _contain: 'Ia~tos.e, microcrystalline cellu-
`lose, cro_spovicj.o:ri.e,·· co)Joida,l_ silicon' .dioxide, magnesium
`stearate, hydroxypr.opyl JAethylc!)llulose, titanium dioxide,
`polyethylene glycol, pqlysorbate· 80, yellow iron oxide and
`red iron p)Qde . .
`CLIDUCALPHARMACOLOG~
`Pharmacody,nam~c Actions: REVIA is , a pur~ opioid antago-
`nist. It markedly' attenuates or completely bloCks, revers-
`ibly, the subjective effects of intravenously admi.D.istered
`·.-·-:_., •
`opioids.
`When co-administered with morphine, on a chronic baais,
`REVIA blocks the physical dependence to morphine, heroin
`and other opioids.
`.
`REVIA has fe:w, if any, intrinsic actions besides its opioid
`blocking properties. However, it does produce', some .pupil-
`l!ll'Y constriction, by an unknown mechanism. _
`The administration of ~VIA is not associated with the de-
`velopment of tolerance' or dependence. In subje'cts physically
`dependent on opioids, REVIA will pre~ipitate withdrawal
`s,Ymptomatology.
`''
`·
`Clinical studies in!licate that 50 mg of HEVIA will qlock the
`pharmacologic effects ,of 25 mg of iJ?.travenously adminis-
`tered heroin for periods as long a;s 2'4 bows. Other. data sug-
`gest that doubling the dose o_fREVIA'proyides blockade for. 48
`hours; and hipUllg the ·dqse·of ~:r;;YIA ' pr<ivid~s: blockade for
`abotl,t 12 hoW,s.
`, · ·"
`· · .
`.
`, _· :
`,. ' --
`.
`·
`REVJ;A. b1.ocks the-effects.- of opioid~ .bf com:P:e#ti:ve b~ding
`(i.e.,' analogous to ··competitive iiiliibitlon· ·of tmzy.ines) ·at
`opioid receptqrs. Thjs make_!! the blockade prod].l.~ed po~n­
`tially surmountable, bu~. overcoming f\ill I_l,altnix~:ri.e block-
`ade by administ;ra,t~on, o!very pig~ do,ses of. opiates :p.a~· re-
`sulted in excessive syillpt<ims cifhistami.iJ.e r.e'Iease in exper-
`imental subje~ts.
`_
`·
`. _ · ' ' ·.
`· ._
`· '
`The 'mechan'ism of action of REVIA iii alcohcilisni is not -un~
`derstood; howey~r, ip_volv~ine~t . of the endogenous' opi~id
`system is suggested by preclinical dl:l,ta: ill: VIA, .an 'opioid 're-
`ceptor ant~gofiist, co:mpetitiv~ly bi~ds to ,sudi :receptors ;ind
`may block the effects. of endogenous opioids.' Opioil antago-
`nists have been shown to reduce alcohol ·c'imsui:nption by
`aillmals, and' REVIA has been shown to reduce alcohol'-con-
`sumption in clinical studies.-
`REVIA is not ~yersive- therapy 'and· does _not cause a d,isulfi-
`ram"like reaction either as a result of opiate use or .ethanol
`ingestion.
`· _.
`_ ·
`·
`Pharmac_okinetics - · ·
`HEVIA is· a pure opioid re_ceptol' ·antagonist. Although well ab-·
`sorbed orally, naltrexone is subject to significant :first pass
`metabolism with oral_pioavailability estimates ranging from
`
`'
`
`.•
`
`. . N....:...CH2-<J
`
`0
`
`I
`
`'
`
`I
`
`. ~~v~-is co~tr~dicated -in:
`
`. .. r
`.
`~-'· .
`1), :Piitients· receivj.ng-~pioi4 a,llalge!:!i~s. .
`.
`,
`2) Patients currently dependent on opioids~ · · .
`3)Pa:tients-in a~,:l_l~~ opioid withW'awiJ] _(see W~QS).
`4) _Any·,indiV:iduru: wJ:w,_has :failed thfl NMCAN ch~l~nge
`test. or who hl;l!? ,a PO§itive -q.rine $Creen for opipid,s;
`.
`.
`5) Any indi~du!P ''Yith a history _of sensitivity to m<;VIA or
`any. other components of this product. It is not k:o,own if
`there is. any -cross-sensitivity with naloxone oz: the phe-
`nanthrene containing opioids:
`_ · ·
`6)' Any-individual-with acute hepatitis or-liver failure .
`w.AR-Nrnas; ·. ·
`·
`,·-
`..
`..
`
`-REVIA:Jtas the capacity to: ca~se hepatocellular. injury
`-when given in e;Kcessive doses; -
`-
`'
`REVIA is contraindicated in acute .hepatitis ·or'-liver fail·
`. ~ lire, and · its· us~ in patients with active liver . disease
`·--' must be'carefully considered iri light of its hepatotoxic ·
`effects.
`·
`,
`The margin of- separation betwe~n the apparently-saf~
`dose ·of REVIA' and the.dose causing :hepatic injury ·ap-
`
`AMN1023
`IPR of Patent No. 7,919,499
`
`

`

`pRODUCT INFORMATION
`
`ears to· be only five-fold or less. RE VIA does not appear
`~0 be a hepatotoxin :at the recommelid~d doses. ·. · ·.
`patients should· be warned of the risk of hepatic injury .
`and advised to·'stop the use of Ri!:VIA and seek medical-
`attention if they'•experience symptoms_ of.acute hepa-' , ·
`•.: · .. -.. ·
`titis.
`· ·' . ·
`·
`,· ·' ·'
`·.: -. ·. .
`
`1
`
`Evidence of the hepatotoXic potential ofREVikis d~rived_iiri­
`marilY' froin ' a 'placebo co~trolled study· in ·whi?~ im:'IA W,~s
`administered to obese subJects at~ d~se 'appr?~~atel~ five-
`fold that recommended for· the blockad~ ?f ~pia'te rec~ptors
`13oo mg per d~y). ~that s~~dy, 5 of~~ 'RE~IA.re~ipien,ts de-
`,,eloped elevations of serum trans~ases (I.e., peak ALT
`,•alues ranging fr~m a low of 121 to a· high _of ~32;- or 3 to 19
`times their baseline values) after three to eight weeks of
`treatment. Although ~he patients involV~d · w~re _ geri.~rally
`clinically asymptomatic ~d"!he t~~sammase levels of all
`patients on :Vhmn follo~"up wa~ o~tamed retUTil.ed;_to (or t~­
`ward) baselme values m a matte~ ofweeks, the lack of an:y
`transaminase· elevations of sim'ilai''maghitude in-any ofthe
`24 placebo patie~ts in.the s::rme · stu~~ is -pers~asive evi-
`dence that REVIA Is· a direct (I;e;; not Hliosyncratic) hepato-
`toxin.
`·
`'
`·. · · · ·
`· · .
`.
`.
`This conclusion is also supported by ·evidence-from other _
`placebo controlled studies in 'which eXposure to REVIA at ..
`doses above the amount recominended for the treatment of
`alcoholism or opiate: blockade (50 mg/da~) ·consistently ·prq~
`duced more numerous and· inore significant· elevations· of
`serum transaminases thah ilid placebo. : Transaminas~ el~
`evations in 3 qf 9 patients witkAlzheimer's Disease who ·re~
`ceived REVIA (at doses up to 300 mg/day) 'for 5 to 8 w'eeks in
`nn open clinical trial haye been reported.
`:
`:
`. ·. ·
`Although no· cases of hepatic fruhit,e due to HEVIA adminis-
`tration have. ever beep reported: physicians are advised t<;>
`consider this as a ' possible risk oftreatment and to use'th~
`same care in prescribing HEVIA as tliey would other' drugs
`with the potential for causing hepatiC injury. .
`. .
`Unintended Precipitation of A~stinence: · .... . .
`To prevent_ occurrence of an acute abstirience·s\n'iarome, or
`exacerbation of a pre-existing subclinical abstinerii:e syn-
`drome, patientsimust be opioid-free for a minimum_ of 7-10
`days before starting -~ViA. Sine~ the absence 'of-cin opioid
`drug in the urine is pften not suffici~nt proof that a patient
`is opioid-free, a NARCAN challenge shpuld be iim'ployed if
`the prescrlbi'n!:i' physician feeis there is· a risk of precipitat-
`ing a withdraWal •reaction following administration of RE-
`V !A. The NARC AN challenge test is ·described irl' the DOS-
`AGE AND ADMINiSTRATION section.
`.
`'
`Attempt to O~ercome Blockade:
`_
`While REVIA is a potent antagomst with a proloiJ:ged phai-
`macologic effect (24 to 7~hours), the.blockade.-pi oi:hiced by
`REV !A is sul:moup.table. This is useful in patients•wHd inay
`require analgesia, but pdse·s a potential risk to ihdiVi.quals
`who attempt, on their own, to overcome th!=l blockadero:Y'ad-
`ministering large amounts' of exogenous· op:ioids:,<:Ii:id~eci,
`any attempt by a patient to overcome th~- antagdrdsm by
`taking opioids is 'v~ry dangerous and may lead 'to a: fataJ
`overdose. Injury may a'rise because the plasma concentra-
`tion of exogenous· opioids attained i=ediately .following
`their acute ad.mi:Qistration may be sufficient to 9Ye.rcome the ·
`c~mpetitive receptor blockade. As a ~::onsequence; the Jti;i,-
`tient may be in inimediate danger of suffering life endan-
`gering opiqid intoXication (e.g~, respiratory arrest, .Ciiccla-
`tory collapse). P1;1tients shoUld be told of the serious conse-
`guences of trying to overcome the opiate block'ade . (Se·e
`Information (or Patients), .. · -
`.
`. .
`· ·
`There is ~lso the ·pqssihility that a. p~ti~~t who pad J:!!l~n
`~eated with naltrexone will respond to lower· doses of opi<L-
`Ids than preyiously use<;l, p~ticularly i,f t~en ip. such · a
`manner that high plas:r;na concentrations rem~p_ in the body
`beyond the time that ·na,ltrexone · e:x;~Jj;s its therapeuti,<; _ef-
`!ects. This could result in· potentially life-threatening opioid
`mtoxication (r:espiratpry compro!)l,ise or arrest, cir~ulatoi-y
`collapse, ek). -Patients sb,ould be aware that th~y may be
`more sensitive to lower doses of qpioi_ds after naltrexone
`treatment is discontinued.
`· · · ·
`Ultra Rapid Opioid Withdrawal:
`Safe use of REVIA in ultra rapid opiate detoxification pro- .
`grams has not· been established (see ADVERSE ·REAC-
`'
`TIONS).
`.
`.
`.
`PRECAUTIONS: .General
`When Reversal 'at REVIA Blocl<cide is Required:. In an emer-
`gency situation in patients receiving .fully blocking doses of
`~VIA, a suggested plan of management is regional analge-·
`SI~, .conscious ·sedation with a benzodiazepi,ne, use ofnon-
`opioid analgesics or general anesthesia. · -
`-.
`In.~ situation requiring opioid analgesia, ·the amo~t of
`?P10Id required may be greater thari ·usual, and the result-
`;ng respiratory -.depression ·may be deeper and more .pro-
`onged.
`.
`..
`:
`. . _,
`.
`_
`.. .
`.
`. ·
`A r_apidl; acting opioid analg~sic whi~h· riiillriizes the du-
`ration ofr'espiratory depression is'preferred. The amount of
`:-alges!c administered should be titrated to the' needs of
`e Patient. Non-receptor mediated actions may occur a,n:d
`
`DUPONT PHARMA/937
`
`should be expected (e.g., facial swelling, itching, generalized
`erytlJ.ema, or_broAch<;>co_nstri!l_tion) presuiri.ably dl)e tp Wsta-
`:ririi;t!;l.ielease.
`.,
`,
`.
`Irrespective ·of the drug chosen to reverse REV~_-blocbide,
`the Pl!-tient should· be monitored closely by appropriately
`trained personnel in a setting equipped and staffed for car-
`diopulmonary resuscitation.
`'
`Accidentally Precipitated 'Withdrawal: Severe opioid with~
`drawal syii<fronies preCipitated by the -accidental ingestion
`ofREVIA have been reported in opioid-dependent individuals.
`Symptoms ofWithdiawal have usually appeared With.i.D. five
`·minutes···of-ingestion of·REYIA.and-have lasted for up.to 48
`hours. Mental s-tatus· changes including confusion, somno-
`lEmce · illld. visual hallucinations ·have ·oc.cUiTe'd·. Significant
`flUid losses from vomiting and diaiThea·haverequired intra>
`venous fluid administration. In all c'as·elf patients ·were
`l:Iosely moiritored and therapy With' noncop1oid.medications
`was tailored to-= meet indiVidual reqi.rireinents:
`: '
`...
`. Use of REVIA does not eliminate or diminish withdraw}
`symptoms:· If REVIA:·is ii:iitfated early in the abstinence pro7
`·cess, it will not preclude the patient's ·experience of the full
`range of signs and symptoms that wou).d ·be experieiJ,ced if
`REVIA had n~Jt- been started: N,'umE]fOUS adverse even~s are
`known to. be associated wi!P. withdrawal:
`·
`.
`Special Risk Patients: ·
`·
`.
`Renal _lmpair~ent: . REVIA lind its' primru:y :metabQlite ar~
`excreted primarily iri 'the ·urine, and· caution is rec'o_Il),-
`mended in administeriii.g_ th~ drug to patients >yith n)na,l ,
`impairment.
`·
`_ .
`~
`_Hepatic lmpai~'1"ent: Cautions s:J;Iould b~ e){ercised . wl_Iei:). ;
`naltrexone hydrochloride is. a:dn:Wiistered to patients ·With
`liver disease. Ap. increase in nalti·exon'e f\.UC ~f approxi- ·
`mately 5- and. 10-foldin_ pa_~ients with compen~;~a_ted anc,l dec-
`ompensated liver cirrhosis, respectively, compared with sub-
`jectS with normai livet _ fun'~tion ha~ been report~ d.: Tl).~se
`data also suggest 'that aiteration:s in. miltrexone 'bioavail-
`ability are related to liv:er disease sev,er:ity ... · ..
`' .. ·~--
`Suicide:· The risk of sweide 'is', known to be illcreased in
`patients with substance abuse \-rith ot Without c<;>ilcomit~t
`depre!lsion. This risk is not abated by treatment' with RiVIA
`(see ADvERSE REACTiONS). ·
`·
`' ·
`·.
`·
`.
`lnforrriatio~--fOr 'Patient~: · It ·is' recoillillehded .th~t the pre-
`scribing physician, relate.Jhe follow:!Jtg informatiop: to pa-
`tients)>ellig treated with rul:VIA:
`· . ·..
`.
`. .
`. . . ,
`You hl;lve b_een,-prescribed. REVIA as 'part ·o:f the · comprehen-
`sive treatmenffor yom:alcoholisnl. ·or drug dependence. You
`should.'cai-&' J.d~iiti~catio'n to alert m~dical pe~s<;>rii:iel to the
`fact. that yol_\_ate tak.ilig REVIA- (naltfei one hydrbc4loride), A
`!tEVIA medication tara riiay_be obtainecffroin yo1JI physician
`·ai)_a caD, b!,l v~edfor _t_l;ris _pi.I:fpo'se: Q~g the identifit~tj.op.
`car_d shoUld h_elp 'to :ensure th.at you 'caii -obtaiD. cadequate
`
`ter~d to a patient receiving REVIA, the amount of opioid
`required may_be greater than usual, and the resulting res-
`pjratory depression may be deeper ~dmor~ prolonged (see
`PRECAUTIONS).
`.
`Carcino_ge~esis, Mutagene~is and lmp_airmenf of Fertility:
`Carcinogenicity studies in rats and'mjce were condupted at
`doses as high as 100 times the 'human dose.' There was no
`statistically si~cant increase.in the ib.cideilce' b(~y tu-
`mors and, except for vascular tumors 1n the RE:VIA-treated
`female rats, tlie iiicidenbe oftuinors obser\red ill the stUdies
`were within ranges seen in historical control groups. REVIA
`W~S negative in bacterial and cultured maniiDalian cell mu-
`tation, in uitro chromosome aberration, and in 'uiuo micro-
`nucleus; chromosome abenation, and heritable transloca-
`tion asS!!Y~· It was weakl~ positive in the Drosophila mela-
`nogaster recessive leth~l'test and gave equivocal· respons~s
`in E. coli DNA repair and in in uitro maniiDalian cell' ifiuta-
`tion and a,naphase chromosome assays. Overall, the study
`results indicate that the genotoxic. potentia], ·of RE:V!N is low.
`REVIA (100 mg/kg, approximatelylOO times the human ther-
`apeutic dose)· caus~d an increase. in pseudopregnancy and a
`decrease in the pregnancy rates of female rats. fl'he· rele-
`vance to th~se observations to human fertility' is not known.
`Pregnancy: Category. C. · · REVIA has been·shpwn to have em-
`bryocidal and fetotoxic •effects in rats and rabbits when
`given in dosages 30 ·and .60 times, respectively, the human
`dose.
`'
`·
`·
`, .. : ..
`The~e are ·no ad~_quate and:well:controll~d studies in preg-
`nant women. REVIA should be used in pregnancy only when
`the potential_benefit justifies the ;potentialriskto the fetus.
`Labor and Delivery: _ Whether or not REVIA affects the du-
`ration· of labor:and· delivery is unknown.
`Nursing Mothers: ·· Whether or not REVIA is excreted in:hu-
`man·milk is unknown .. Because many drugs are excreted in
`human niilk, caution should be exercised .when REVIA is. ad-
`ministered to a nw:sing woman~ ·
`· .. . e~djatric Use:. The safe use of·REVIA in pediatric patients
`yoiinger·than rs years old has·not been established.
`. .
`ADVERSE REACTIONS:'
`During two ·rando.Jni:l;ed, double-blind. placebo7c~ntr~Iied 12
`week trials to ·evaiuate the efficacy ofREVIA as~ adjunctive
`tr~atment of alcohol dependence, most patients tplerated RE-
`VIA well. In these ·studies~ a total of 93 patients -received RE-
`VIfo. at a• dose ofqO ~g once daily. Five 'ofthe!:le patients dis-
`continued REVIA because of nausea. No serious adverse
`ev~nts . were repq).:ted d~g these two tnais . .. --
`.
`While extensive clinical studies evaluating the use of liE VIA
`in detoxified, formerly opioid-,dependent individuals failed
`to' . .identuy any single, . serious untoward risk of REVIA use,
`placebo controlled studies employing up to five-:t'oid hlgher
`5~~,~~~:.~ttr.,~:;~;;~~~~~th~:~~!i:t; .
`doses of RE\];IA (up ~0 300 mg per day) thau that recom-
`mended for use ill opl.ate rec:eptor blockade have shown that
`ru;VIA causes hepatocepu1ar injury in a substll.Iltlal propor-
`tio,n 'of patients exposed at higher doses (see .WARNINGS
`aii9, P~CAUTIONS: Laboratory Tests).
`. ·
`.
`·
`.ASide :from this finding, and the iisk. of precipitated. opioid
`withdrawal; .available evidence dqes not incriminate.REVIA,
`used at any d~se,.:as a CaljSe of ahy other serious ~dverse
`r~action for the patient who is "cipioid free." It is ci:itical .to
`,recom_llze_.that HEVIA ,can pre~ipitate or exacerbate absti-
`nence ~igns and symptoms in an)' individual w:P,o is n_ot cpm-
`,pletely fre!=l of exqgenmis ,opioids.
`-... :;
`. ··
`_, ·.
`Patients with. addictive disorders, espec~apy ,opioid. addic-
`_tio:J;l, are lilt I~Sk ~or mtiltjp}e numerous adv~rse events and
`~bnorlnai iliboratory findings, in'i::luding liver fun.cti'on' ab-
`normalities . . Data· from both controlled and observational
`studies suggest . that these abnormalities, other . than the
`a:ose-related-iiepatotoxiCity des~ribed above, are_not reiated
`totheus~_ ofREVIA. __ . ..
`. - ...
`. _,
`· · .. .
`.
`Among opioid free individuals, REVIA administration at the
`reco=end_ed cj.os~ bas not been associated with .a predi~t­
`abl~ profile· o_fs~ri9.1JS. adverse or untoward events .. However,
`as_ mentioned ~bov~, a,JtlOllg individuals using opioids, REVIA
`may cause serious withdrawal :r~actions,(see· CONTRAIN-
`DICATIONS, WAJtNINGS, DOSAGE AND ADM:I::NIS-
`TRATION).
`.
`..
`...
`.
`..
`Reported Adverse Events
`REVIA has not bee~. shown to cause signifj.cant increases in
`complaints in placebo-controlled trials in patients known to
`be free of opioids for more than 7-10 days. Studies in !Jlco-
`holic populations and in volunteers in clinical pharmapology
`stUdies have suggested that a small fraction of patients may
`experience ap. opioid withdrawal-like symptom complex .con-
`sisting of tearfulness, mild nausea, abdominal cramps, rest-
`lessness, bone or joint pain, myalgia, and na,sal·symptoms.
`This may rep,resent the unmasking of occult <;>pioid_ use, or it
`:q~.ay,represent· sympto!IIS attributable to rialtrexone. Anum-
`per of alternative dosing p;itterns have been rec<;>mn:tended
`to. try to .. reduce the frequency of these complaints (see In-
`dividualization of Dosage).
`·
`·
`·
`Alcoholism:
`. .
`In an open ·label safety study with appro~ately S70 indi-
`viduals with alcoholism receiving REVIA, _the following new-
`
`Yini should'tike REiY~as db.;ected..by your-physician. If'y'ou
`att~'mpt t~':Skif-adfililrlster h~{oi:i'J. or ap.y othe:r' opiate drug;
`in small.doses while on ru:Vi\, _.you . w.il~· no~ per~eiv~ any _e!-
`~pt. Most ·important, how~vef, if you il,tteiniit to self-~