LDLK&M
`LIBRARY
`600 COLriH foN~t WEST
`V/~;~;rt~·l~L.O, N;.cl 07090
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`RECEIVED
`NOV 2 2 2.004
`LDLK&M
`
`59
`2005
`
`EDITION
`
`PHYSCANS'
`DESK
`REFERENCE®
`
`Executive Vice President, PDR: David Duplay
`
`Vice President, Sales and Marketing: Dikran N. Barsamian
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`Lois Smith, Eileen Sullivan, Richard Zwickel
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`Project Editors:. Neil Chesanow, Harris Fleming
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`T H 0 M S 0 N
`•
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`Copyright© 2005 and published by Thomson PDR at Montvale, NJ 07645-17 42. All rights reserved. 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
`P DR
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`Nutrition and Health" are registered trademarks used herein under license. PDR" for Ophthalmic Medicines, PDR"' for Nonprescription Drugs ar1d Dietary Supplements, PDR"
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`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 PDR0 Electronic Library are trademarks used herein under
`license.
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`Officers of Thomson Healthcare, Inc.: President and Chief Executive Officer: Robert Cullen; Chief Rnancial Officer: Paul Hilger; Chief Technology Officer: Fred Lauber; Executive
`Vice President, Medical Education: Jeff MacDonald; Executive Vice President, Micromedex: Jeff Reihl; Executive Vice President, PDR: David Duplay; Senior Vice President,
`Business Development: Robert Christopher; Senior Vice President, Marketing: Timothy Murray; Vice President, Human Resources: Pamela M. Bilash
`
`ISBN: 1-56363-497-X
`
`KASHIV1067
`IPR of Patent No. 9,492,393
`
`

`

`BETASEPT® .Surgidal Scrub
`[ba·'ti'ih-sep·t·",J :,,-_, .c--,'
`--'-' ·
`(chlofhexidirui glu~~nate) ·4%~";' ,, >' -'
`~.: r:-.
`
`OTC
`.,;
`
`• · , ._
`
`•
`
`•
`
`• • -
`
`0
`
`.• .. · •• j
`
`ACTION_AND USES
`1
`BETAsEPT :Surgical Sc~b\~hl~rh~rldk~ gflifonat~)' is ~
`antiseptiaii'ntilnicroEi81 skin '~1\'l~S!'lr fof }i@d llcfi'II:i!:>hig or
`w::.s~JW.g 'by_Qpera#ng rog;w, ;I?~#)niiei_, for 'b.aiia7foa~~g hr
`~edical personnel, for· pre~operative . .Sign preparation, and
`·:
`for skin wound and general skin cleansing..
`.
`·.. -·
`BETASE;PT,Surg:\cal Scrub .provides rapid )Jactepeida1 ac~
`tion and has' a persisfent iillti:iiricrobial effect ag~t"a wide
`:i:~gj'o(~c~oorg~sins/..
`,: ,·, '
`';
`ADVANTAGES
`BETASEPT Slirgrcai Scrub is forirnilat!Jd ift a highly vi~c~iis
`base which can help reduce waste' and per-use cost 'dUring
`prepping and hand-washing. No pink tjnt hils ]:Je'err 'adiied.
`rihiEcTioNs :Foifus:E · -
`' ·· ·
`· · ---·
`-
`· .. , ..
`Surgical Hand Scrub:
`, .
`. . · _
`.
`Wet hands and. forearms with w!lter. Scrub for 3 mlliutes
`with ab~ut' 5 .mL of-BETASEPT Surgical Sc~b ~d a' W:et
`b~~fi,-pa:'~g ':P!rrf:icul~ _attentipn to th,e.nails, cuticl,e,s ~d
`interdigital :?pf!.ces. A separate naiLyle~!'lr :Ii:lay be:-qs\'ld.
`Einsl},.thgr~ug"!lly.-W,ash for an_additi.oJ1al.3.~u~~-V(it!:>,
`q niL of IIETASEP'J' Surgical Scrub and ~se.;unqer run-
`~-[ "'aJ~r. pr:Y -~h~ro11_g~y: --
`·
`-
`_
`.. __ ·
`-·
`._
`.
`..
`Pers~u;mei-Hand Wash:
`.
`.
`. . .
`.
`'·
`W:et-handfi with \vater. DisP,e~s\l_~bout 5 mL ~f~ETA.SEPT
`Stirgical Scrub into cupped hands and wash in a vigorous
`·
`manner for 15 seconds·. Rinse imd dry thoroughly, ·
`Pre-Operative Sldn Preparation: ·::! ·' ' - '' · ~~~ ·- -''5
`-
`Apply BETASEPT Swgical· Scrub.-Iiber-ally:to surgical site
`and; swal;l for at lea§t 2 niinutes. Dry With a .sterile towel.
`Repeat procedure for.an ad_ditional2-minut.esand-again dry
`with-a sterile-toweL··
`·
`·
`-
`Sl<in Wound and General Sl<in Cleansing:· ...•.
`Wounds which involve more than· the superlicial:Iayei:s. of .
`the: skin:shO'uld not be .. routinely treated -wjth.BETASEP.T
`Surgical Scrub; :BETASEPT Surgi~;al: ScJUb' shoUld• -not.• be
`used-for repeated ·general-·skfu~cleansing·o£large body areas
`except·in·-thor>_e patients:wlJ_ose underlyi:D.g·coriditi'on makes
`it necessary to red1,1ce the bacterial- popula:tion. of the skiri:
`To use, thoroughly rinse the,area to be: cleansed with water:
`Apply the minimum amoiint--ofBETASEFr Smgipal• Scrub
`necessary to cover the skin: Dl' wound 'area and wash -gently.
`Rinse ~;~gain .tho_roughly.
`.. " ,
`w.i\itNI'NGs · -' _.
`· ,, ·-
`.
`FaR· EXTERhiA'L osE'ol\ii:v,- I<EEP'o-ur of: EVEs: EARs
`AND MbUfi:f; BETASEPT SORGI&At 'SCRUB SHOULifNOt
`BE USED AS A PRE~OPERA;il\lE ·s-I<IN'PFi,EPARATION-OF
`THEM FACE .OR HEAD~~MiSUSE dF PRODUCTS CONTAINiNG
`cliu:>f\Hi:xn511\llf' <;tucciJ'iiA-.:i:• w~·s··~i:EN ·REPORTED to
`CAUSE SERI6us:AND-;PEFUiiiANENt EVE INJUJW'WHEN -IT
`HAS BEEN PERMITTED TO ENTER AND REMAIN" ll'il THE
`EYE 'DORING suRGicA[ PR6ceouReS.IF sr:iAsePr'suR~
`GICAl: 'SCRUB. SHOVLO:'C'ONTA'~T'iHESE ~AREAS; RINS'E
`OUT PROMPTLY AND THOROUGHLY WITH WAt-i:Rt·:· : ·- '
`Avbid :corita"'C~ ~iiVi'tJj rneriinge~~·"!B~iasept ~Surgicai'Scru'~
`should not be-used by persons who have sensitivitY, to' it or
`its'·comp·o-~ents: ~Chlo~hexidine • gli:icoilati has' beeho''re~
`ported to c;ause deafness when instilled in the ·rfim_ali!reilr
`through p~rforated> !'Ill~ ·<Jrums, ,lrritatioil: ·seii~1tizatiolf- ~nd
`generaiizetf :aJh~~gic reai:tion't•.ffave'?bi!en · ~epor.t·e<!''With
`chlorhexldine-containing pro_du(!ts, especi_aiiy in th~ g~nital
`
`~~~~a~~~:~t*f:~~~~~~i;~;~e~i~f~~~~~~~~1~e~~
`gestion;:s~ei<'-'J)rofe~sjbnal, ·ilssi$tari~~'or 'contac~ a Polson
`~~:i~o~~~!1~~1fie~~~~!~!~~~:~;-,. 7_,
`,_ '":,~;~-:\ "", --"
`· .. :
`'·· ·<n · · .. · ~:. ~,:;-:.·~:: ---.: · .. :,: _:rr;.-.~~-
`, -
`hv.(.!./t
`-~~ ti.
`HOW SUP:f~IED -.-\p-. , ,
`": c.·~ -
`.
`,
`,
`-
`.
`BETASEp_r® Slirgi~M· S,c:i:~b·:~:-is .packaged in -1-~allci'n;-3.2
`oz., "32_oz. with pUm:p;·il6 o~:, 8_.oi;{. and 4 oz.plastiailiottles.
`Copynght 1993;•2004tThe-Purdue -Jg-ederick.Company, ·.1 ..
`Stamfot'd;· €T, 06901·3431.si•;D:·;. -r;
`_, :. · -., :- '_.,
`
`, , .
`M~,coruftru® ·
`..
`tl?i§~~~Ii'-trnJ . . _ .
`< , .. ,
`(JV19rphi!Je Sulfate f:,q!ltrolled-Relea,se) Tablets,
`1,5 n;Jg ~.o lll9-P0 11!9 ~oo lll9 ~OQ.Ill9*,
`
`OT00001C c;~:,
`-aoos!s-otHioi -
`DESCRl:PTION
`Chem1cally, morphine sulfate is 7,R-didehydro-4;-5cr-ep'oxy-_
`17-methylmorphinan-3,6cr-diol sulfate (2:1) (salt) 'pim'tahy~
`drate and-has'thefolloWiilg.structural formula: -.
`,_
`-[See chemical-structure-•at'-top of next column] ·
`. = ---
`Each MS CONTIN '15 mg·'Contr~lle·d"&ilease Ta:blet con-
`tains: 15 mg-Moi::phine sulfate USP. Inactive ingredients: ce·o
`tostea:tyl alcohol; -FD&C blue No.· 2, ·hydroxyethyl cellulose;
`hydroxypropylmethylcellulose, lactose;•magnilsium stea:~
`raM, talc;cti_tanium dioxide, and other-ingredients. "'-
`Each MS CONTIN 30 nig Controlled-Release Tablet con-
`tains:: 30 mg Motphine sulfa:te USP. Inactive ingredients:• ce-
`
`PURDUE FREDERICK/2807
`
`. ,-:
`__ ,:
`Pharmacodynamics
`The effects described below aie coD:rmon to all' morphine-
`containing products.
`Central Nervous System
`.
`. . __
`The principal actio_ns pf therapeutic value,ofmorphine are
`analgesia and sedation: (i.e·., sleepm~s~:~4iiiXioly~is). ~-~
`The precise mechanism of the analgesic action-is unknown.
`Hu~eti:!'~~ ~pe!iifit- 'C~S op'iat~ ~eceptol'~'' iilid' ~ridog~nous
`co~p6¢i:ds yn(l}. ~orpWne~lilte ,activity have been id~ntifi~d
`~P'2f!ghout t~e,hr!iih !lld sp!Jlru cor~: and. ar'c:Jlikely to_pl~y
`a role in 'the e~ressio'ii of a:imlgesic effe·ets: .
`. . .
`: .
`Morphiiie !>i'o·dtice~. respiiatm7 'depi-es:sion 'bY, direct. a~tio:ii
`on brain stemrespirat()zycenters; The'.fuechahl.inn ofre~P.i­
`ratbry depressididn\ihives a reduction in the responsivene~s
`of the brain stein: respitaiorf~enters to incre'ases hi cai:iiori
`dioXide 'tension1-and'to ele•cmca} stiiiiulatlon..
`.,
`·.
`·' I'
`Morphine depresses the'cO\igh·refleiby-direct-effect on the
`9~ugh c~nter_ in cti).e jlled.ufia. A,l,ltitussive 'effects 'lji~y -o~cur
`with doses lower than those' iisua]ly required 'for. anhlgesia.
`Moi-phlne caus'es. rtliosis, everi 'in total· datbiess. Pfu:pbint
`!:~~~ re:;.~ ;~~~~1:~~!c;;~~t~itt~f~~~~~E~!t~~~
`giil.s _ i:nay. produce simMr ·:findings).-Marked_ :m:Ydiiil'sis
`),"ather' than mios~~1may b~ 's_eeli With worsenini, P.Y'P~xi.a:_ -
`' i-
`Gastroiritestillal Tract aiid"Othei Smboth·Musde"'- ·
`:~~t:~~::~~fitj~=!~&!~~~,~~~~~f
`'and duodenum. Digesti6h of food ill'the_ small int~stin'e is.
`delayed and propulsive contractions are -decreased. PrbpUl~
`sive" peristaltic waves ill the colon are '({~creased, while tone
`15 :iricreas'ed to.'the··:Pomfofspasm, The emf ;result is coiisti~
`:Pation: Moi]ihille ·c:aii-. cati~e -a marked inc'rease' m bilia.tY:
`trai:i.ptessilre r ii~ 'a result of spasni of sp:hlncter of 6ddi. · ·'
`~"' · .. :·· ,
`.
`cfu.dioya¥§ui'ar:sfsteiii· · : · _ _ _
`Morphine produces peripheral' vasodilation which, may ·reo
`sult in orthostjltiC hypqteri~lOJl. R,e~eaSe ofhistfi.mme' can ~OC~
`cur arid' miy'2i:ontrib)ite' t'O''narcotic-iiiduced hyPotension.
`M~nifestations Cif 'histamine releasE!_' aridior -pe#pb,-e.ral
`vasoffilation· ·may iriciuae '_in.-ui-itus,~ flushing;' red eyes; ·lind
`.:.''' ;:,,_-.,-_,
`_·
`_ ·
`·
`sweating.
`·
`·
`:.
`Plasma Level-Analgesi8:-ReTa'tioiiships-·" '
`,.,. ·
`'
`Iii an); particular patient, bdth analgesic effects and' plasma
`morphine' concentrations are relat~d' to the' in()rphine dose:
`:m non:..tolerant iiidiViduals, plasma morphine concen:tra:
`tion'efficaiiy relatioilshlp:Efhave lieen demorisfrated .and sug:-
`gest that' 'opiate recepton;' occupy·''effector compartments;
`leading to a Jag~tinie, :or hystefesis; between rapid' dhanges
`in plasma morphine concentrations and the effects 'Df such
`changes. The ·most· direct ;and prediCtable ;concentration~
`effect relationships can, therefore, be expected at distribu-
`tion·· equilibrium and/or steady~state cop.ditions:-In general;
`the minirimm effective· analgesic .concentration in the
`pJasma:ofn,on-tolerant patients ranges from approximately
`5 to·20 n:g/mL.:-
`· • r·- ·
`-
`..
`While plasma· morphine~efficacy· relatioriships _canobe ':de~~
`onstrated •in non;tolerimt' indivic;luals·; .they .are influenced
`by a wide variety offactor.s'and:are•not generally'useful as
`a guide to the clinical use of mori:Jhine. The effective dose in
`opioidctolerant patients-may be. l0c50-,thnes_as great (gr
`greai;er) t4an ·the appropriate:·dose for opioid"naiv.e iridic
`vidl."!als.,Dosages of niQ:rphjn:e should be-chosen· !pid-:iri:ust be
`titrated on the. basis of clinical evaluation of the patie.nt and
`the balance between_ therapeutic a:n.d adver~e effects> .... ,
`Rot ,any .-fixed dose and do_sing -interval, MS. CON'l'IN- wPl
`haye- at: steady.-state, a, lower:Cma-.: and a highe.r Crili,; -than
`converitional morphineShi.sis- ivpotential advantage; a:re~
`duced fluctuation.in m!l_rphiiie concentration:during the dos-
`ing. interval should :keep . .:~norphfue b_lood levels :w.or~ cen,:
`tered , :wit.P.i~ "~the , ·t.heoJ;eti(:_al- _ "tb,erap_et1tic --wi~dow. ~
`Ofluctuation:_for a dosing intervat is qe:fi:p.ed gs [Cn.ru.:Cmml/
`[Css-p_verage].). Q1;1 the, othe-r.l,land,_the, d~gree,of fluc~ation
`in seium morphine concentmi;:ion _ypight <;Onc('!ivably af(e<;{
`other phenomena. For example, reduced fluctuation!;;~
`blood morphine.;cop.centrations might infh1ence.the rate-.o:f
`toleranc~-mdu~tion: -'-'
`·
`· · · ·
`··
`'·
`· · ·
`~ ........ , ,-
`The elimination of morphine occurs primarily as renai -~~­
`cretion' of3-morphi.he. glucuronide: A small-amount of-tb'e
`glucuronide conjugate is excreted in the bile, and thilre 'is
`some _.minor ,enwro}).epa,ti_c';recycling. ·Because -~orp!:>,ine. is
`primarilymetabo.Ji;zedto :in~ctive!!letabolit!_ls, th,e effectl!of
`re!:l~l.:!;l,isea~:~!>:O.!l mo_:t;ppine's-,elimination ar~ not.likely,to be
`pronoun9,eq. J!gwever; ·as with _apy: gmg, cauti,o~ sho,uld be
`taken to gulll'cl. against ·unantipipa.t!l,d _accun;rqlatiQ:q)f renal
`and/or ,h('!!11ltie;fimcti,on is. s~riom;ly ii;I;tpair,ed,:-:
`.1 ;.- ·
`INDICATIONS AND-USAGE
`MS CONTIN is a controlled-release oral morPhlne ·rrirmhia,
`tion indicated for the relief of moderate to sexere. pam.:Ifis'
`intended for u1e 'ill' patients who reqmte''i-ep!3atei:i. dosing
`with poteJ,lt opioid anhlg~sics over.periods iir'i:nore th'il.ii a
`fevfdays.'
`·:o,.-
`·
`"" · '-- ' •
`-
`'i'he :Ms CONTIN- 200 mg'tabiet strength is a. high dose;
`cob.t:i:olle~-r~lease, Oraf mprphfue formulation 'illdicated for
`·
`tlie:relief or'pain in opioid"tolerant patients oilly. · · -
`QQl~TiiAil~mcAT):QNS . : . -
`-~ . - . " -, --<.J
`MS CONTIN is·conti:airidicated in patientS' withJmown:hy-
`per~ensitivitfJto the drug, :iii--patients with respiratory de~
`pression :in the absehce of resuscitative equipment, ·and: in
`patients with acute or severe bronchial asthma;
`-MSCONTIN·is:contraindiliated in any patient who has or.is
`suspected o,~ having a paralytic ile_'\IS_;
`. Contfnueci on next piige
`
`Consult 2 0 0 5 PDR® suoolements and' future editions for revisions
`
`i~stearyl alcohol, D&C reci''i-ici.'·7, Fn'&c 'lil~e N~. i. hy-
`droxyethyL ,_cejlulose, • 4ydroxyp_ropy:l ·ll'ethylc~IMpse,
`l~j-ctos~, ~1;1~e~ium~st~arate, talc,;~~ani,ll,I!l .di~xidec ~d
`. c_
`other lllgre.ctients:
`;;· :, .,
`'
`--~>-
`:,, ;.,
`'
`·-·
`Each 'M!S: QON'J,'Il'{, 60. mg, Qop_trol~e[l-Releiise. Tablet con-
`truns: 6o~g _M9,i-pb,ine flul:fa~e ut'l;p. _I:q.a!!tive ~ire4feiits: -~e­
`tostea:rYl illcohpl, :p&p red Np: 30, P~9:iel_loi ~q: c~01;!fY:::
`droxyethyl , eelluJol:le, hydroxyprop_yl met,hylcf:!l]}llo!le_,
`l9,ctose, m§lJ~:ilesium.(~tearate, talc,. ti~anium .@ci~cl.~. ~d
`other ingredients.
`:BJa,ch¥~ CQW~-1op-n1g :contJ;oJl~d~~Ieas~ Tabi~t,~im­
`tains: 100 mg Morphin~; sulfat~ !{SR:;'Jnacp~e R;l_gr~c4e_nts;
`c:etps,~e_aryl li1p>hp~._ ,hydJ:o:JCX~tllY:~ .. c,E!ll1Jl~~-e1 -hYc_dro:zypropyl
`m.eth:Y!SE!JlulQfle, :wagnesl~:s.ttLara~e, s_yn,tl),etic ~Iac;k iron
`oxide, tale, titanium dioxide; anq,.qthe_(i;!_gre<J.!.I:lnt!! . .r
`M.~ COI\I1JJ\l200.,mg.Jabl~,t_~:;,' c,.,_;-,rF.,pj_<: Ci'.'. ·"·~[,;.
`,.;
`(F()r ~~e i,n ()p!oid-tolerant pj!tients·,oniYi: ,~,.
`-.... , ,_ .-
`Each Ms' CONT.IN 200 -mg co'ritrolled-Reiease Tablet~: cori:
`t~insi 200 )!i~( M~rphi~~ su'ifat~--.u~Ktn~:c~ive. ina~idieritsi
`cet_osteilryl ii_!cohoi,;~&G.. yeii~""''-NP~;10, .FD&C ~lue; Np, ,1,
`hyd_roxyethyl cellulose,. hydroJWpropyl .cellulose,. bydroxy-
`propyl methylceltuiose, mag~e~fu'~~~e~rat~;. i:J~tY.E;~hv1eii~
`gly_col~ t~lci.11!1d_Jitaniuom (.i_i<!Xide., J . _, ., :-
`'. :·':;,i-,
`
`:"FOR USE IN OPtolf>A:oi.ERANT P.ATIENTS ONLY."
`
`. ·
`
`t~~c~-p~col.o~i;·_,=:·-- .... ·-· ,_,.
`Pharmacbt<iii,eiics'·and-Metail·d•ism' :.:
`MS CONTIN is a ~<liltrbllkcl.~release t11blet cont$rihg Ijlor:
`phine sulfate .. Following oral adn'linisb:ation ot'i.i'giveri dose
`of.in~q)hine; the aninb'nt 'jlltimiitely absorbed is'·essentially
`. the sanie whether tii~.~6lircti is":Ms CONTllfor a conven-
`fi~na}_formul~#Qri; MqJ:pJ.l!tie, i~ released fiom M:s- c_i;mi'rn
`E!OJ#~y<lha,Vmotti 'slowlyJh'an-frbm .conv~ntional oral prepa-
`rations.· Because of pre'-systemic 'elimin~tiqJ;l (i.e.; ffi.etabo-
`lls:tn_in the gut w.all and liver).only about ~0% of the admin~
`
`~!~~l~tt~~rj~::~~~i1¥~~r;r®t:e;~let~_pi~s~~e~
`kiilneys;-liv(lr, intest;iriiil tta:c_t,-1\ings,. spleeti; att<;l brai:t;~:
`· Morphiiie"il)~o· eros!i7s' the placental'. Jiiembr3.p.es, anc;l has
`m:o~~~;~~~r;~~~: (l~s~~:t~~ §~)'of•~orp~1. i~
`deiiiet'hy1ate'd;7for· ill practical p1.Jljio~e_s;~vir.t)J.al1Y:<!lr :¢qi~
`phin,C? j~ c?!l~~fi;ed -~q gTu\i:u~onide .1ll~fabolj.te~;),mong_these,_
`riioi:Pllii:ie.~3"glucrir.onide is presiirit in tli~.liigliest 'plasma
`!W:c~i~~;~1~~~~l:!JJ!,·:;~~~~~~~~;·.an~-i~·not
`ea§lJY satu,r,l!-ted; e_v.e1,1,in \Usease.., Tl:le.~efore,, rate, of delivery
`of morphirie· tO the gut and liver shoiild nof irifluence th-e
`total :!',D.~. J?,t;obabJy, the relative. qwmtities of the yarious
`metabolites formed. Moreover, ev~ni.:lf rate- affected -the rei:
`?tiv~ a:.mC?un~~}fe.llch, metabolite :f~VJ?:ed, i(sli~'Wd be,~:
`~portf!P,t cliili"ally.because 1llOUJhin!l's Ip.!>tacpolites are qr"
`:eaJ:K~~:~~~aqo~~t!c .iar~~~;s. s~9.W;~~on~;d~~J
`
`able inter-subject variation but are represe~tativ:e. of a~er~
`age values reported in the literature. The volume._of,distri~
`b_]l_tiwi (.Vd) for niqry}Jllie" is 4)t~r~._per IdJ.o~!ini~:AAd)ts
`~~al-~lj.lllirtati9J:!:half-life is_nq:t;Jllal!y2.Jo 4h~~s. _
`Follomng jill_~ ad.miJljstr\1-~on qf.~onven~iqnalt,>~~ moUJllp},_e
`p_ro~uetl!i-~pprQxpnS:FJY fifty 11erc:!lnt of the.morp~e .th~~
`will reacb,-.tb,-e ceJ;ttr1ll !!O!!fpru:tme~tintllct pe,a.-c_ll~§)t withi!l
`3.0 )ni.nytes. FoUowingJ~e ._aJ!tninistr:l:!,t~on.:of:,!!ll e,_qual
`a,mojpl~ ~fl M~ QO,&Tfl\1 Jo _norniat-y:o~unteers,):to~e:ver, tJ:Hs
`e~jilnt 9f,~bso_ri>tiQri O$!_~ur,-,p,n average, afl;e_r ).~ hOll.l'S~, ,;-.
`· The po;;si_Qle;~f~ct!lf-fopd :upo,n, the syst\')mi,cJ~foavailabilj.ty:
`of MS CONTIN hall· not il;leen .SYSUlgJ.atically ~V~Ull-ted fQr
`all str,ength,s; 'Da;lia_iro:D;l:at 1'/a!lt:o.n_~ s_tudy;sugg~sts:that
`cogc1,liTent !l~il3t_ratjon o~MS CONTW with a fat~y m\')al,
`may_ 9llUSe-:a !?light. qeQreas~sip:pe_ak -plas.ma CQnC~nia·!ltiQn_.
`Variation in the physicallme.chailiclil properties of a .fori:n]l-
`lation of an oral morphine drug product can affect both ;its
`absolute bioavailabi.;Iity ·and 'its :absorption Tate constant
`(k;,). The- formulation: employed in MS CO:NTIN has not
`been·1shown to affect morp.hine.'s- oral bioavailability,:but
`does ._decreas.efits apparent-k,. Other basic pharmacokinetic
`para,m.eters '(e.g., .volume-; of distribution [Vd]; elimination
`rate -constant -•[kJ, cie_arance [Cl]), ate. unchanged as-,they
`are fundam~ntal.properties,of morphine .in- the organism:
`Howevel'j,in Chrome use, the possibjlity_.that.shifts in metab- .
`olite to. parent drug ratios may ·oc(:ur_ canno_t_be excluded;_-.
`When immediate-release oral morphine or;MS CONTIN is
`given on .a -fixed dosing regiinen, steady•state' is achieved in ·.
`.'".: :->·
`about a:day. -__ -:-
`., .
`For a:give1fdose anil dosmg iiiterva!f:tlle AUC and .average
`blood concentration of morphine at steady-state ;(Css-)..will
`be ;independent .oftlJ_e specific' type. of oral .formulation ad-.
`ministered so-long as,the forniulations have the same- abso;
`lute bioavaiiability. The absorption: rate of a formulation
`will, however;" affect the :maximum <Cmai) and IDinimu:in:
`(Cnri,):blood levels and the-times of their occurrence. -· ·
`
`KASHIV1067
`IPR of Patent No. 9,492,393
`
`

`

`2808/PURDUE FREDERICK
`
`M$ Contin-Cont.·
`
`WARNINGS
`(See also: CLINICAL PIIARM:AdOLOGY)'
`Impaired RespiratioJJ ·
`.· ·
`.
`' · : .
`Respiratory depre~si~D. is. the chief h~ziird of a.J.i fu.§.~p~e
`preparatimis:. Re~pll,'atoi:y depression occilrl'! _most ·r~e­
`quently in'the.elde}:ly and debilitated pa:tieii.~S.I).S well.af?.m
`those suffering froni condition~ accompliJl,ied liy hypox:ia or
`hypercaP,nia when even moderate ther~I!elitic; doses inay
`danger\msly decre.¥e puln!onary ventilation, .
`'
`.
`M0rp~e should lie used, \yith extre~e cauqo~ in patients
`with chionic obstructiv.e "puJmo:Q.ary dis.ease or cor puhno-
`n:aie; and in·patients.having a sub~tantiallydecreased re~~
`piratory reserve, _hypoxia, hyperc~pnia, or pre-existing re~~
`piratory depression, . In such patients;_ even usual
`thera;p:e~tic dosef? of, moiphlile ma:y decr~ase respirat6rf
`drive while siniUJ.t!llleOUsly mc,reasing airway resist!ffiC\) to
`the point of apnea,.
`. . . .
`' ' .
`.·
`.··
`.
`. .
`.
`He~d hiju'r-Y and h'lcr~~sed lnt~a~r~~i~IPfessure
`.
`·
`The respiratory depressant effects of morphine with carbon
`dioxid(;l retention and secondary elevation pf cerebrospinal
`fluid pressure niay l:)e markedly exaggerated in the presence
`of he.ad injui,Y,. o~ller mtJ;acraruru .le.s~ons,' or pre-eiistfug lli-
`c:re(lSe in intra.crariial ·pressure. M:o.rPhirie pro~uces .·effects
`which may obscure l).eur()lOgic s~gns offurlh~r increases in
`pressure in patients Wi,th head injuries,.
`.· · .
`·. ·
`Hypotensive Effect
`.
`·
`. .
`. ·
`. ·
`.
`:t\18 CONTJ:I\r, like all_ opioid an!llgesics, may ca-q.lle sev~re
`h:YJ)otension in an 'individual whose !lbility to mamtain his
`blood press~e has already beell. compi~mised·by a depleted
`blood v:~Jume, or a !!Oncurrent adinii:liStrati_cm of driigs E>ucj:l
`as phenothiazines or genei;al anesthetics.:(See alflo: PRE-
`~,AUTJON~; Drug Interactions.) MS CONTIN may produce
`. . . . .
`orthosta~c hypotension ii), amoulatory patients,
`MS CQNTIN, like. all opfoid analgesiCs, should be admims-
`tered With ca.~tion to patients hi circulatory"shoc:k; siri.ce, va~
`sociilatlon produc~d by thf) drug mily.furj;ner r(;!CJ.uce caidi:ac
`outpl.lt and blood pressure..
`. .
`. .
`.
`··~
`Interactions with other CNS ·Depressants . .
`. ...
`.
`..
`MS. QON:TIN, like all opiQi<l analgesics, ~hop.ld. be used ~ith
`gr,eat 'ca]Jtion ,and in requced dosage)p..'patients who are
`concurrently receiving other cenj;ral :nervous systen1 CJ.epres-
`santsjncluding seda.tives-or hypnot~@; gep.eral anesthetics,
`phenothia~i:Q.es, _other .tranquilizers, and alcohol becaus,~.
`respiratory depression; hypotension, and .profound sedation
`or coma may result.
`·
`·
`Interactions with Mixed Agonist/Antagonist Opioid
`Analgel;ics
`From: a theoretical perspective, agonist! antagonist. analge-
`sics (i.e.; pentazocine, nalbuphine,. butorphanol, and bu-
`prehorphine) should NOT. pe administered to a patient who
`has received or is receiving a course of therapy with a -pure
`opioid agonist· analgesic, In these· patients, mixed agonist!
`antagonist ·analgesics may-reduce: the 'analgesic. effect or
`may precipitate withdrawal symptoms,
`Drug Dependence·
`Morphine can produce drug dependence and has a 'potential
`for being abttsed: Tolerance ·as well. as psychological ·and
`physical dependence may develop upon repeated adminis-
`tration. Physical dependence,.however, is· not ofparaniount
`importance in the management of·terminally ill patiimts or
`any patients m:severe pain. Abrupt cessation or;a·-suddeii
`reduction in dose ·after prolonged use may result· in with"
`drawal symptoms. After prolohged· exposhire to opioid anal.
`gesics, if. withdrawal is necessary, .it· must be undertaken
`gradually, (See DRUG ABUSE AND DEPENDENCE:)
`Infarit:s'born to mothers physically dependent ·on oj:>ioid an-
`algesics· may- also ·be physically depeiident and exhibit res-..
`piratory depression and -withdrawal symptoms. (See DRUG .
`ABUSE AND DEPENDENCE.) ·
`·
`·
`·
`Other .
`··
`·
`:
`Although extremely rare, eases of anaphylaxis have been
`reported.
`PRECAUTIONS (See 'a.Js~: CLrNICAL PHARMACOL-.
`...
`OGY)_
`-
`. Special precautions regarding MS:CONTIN 2oo·mgTablets
`MS CONTIN 20ihng Tablets·are for us!!''tmly in opioid·
`tolera'nt patients requiring daily moiphine 'equival~nt dos"
`ages of 400 mg or moi'e. ·care'should·be tai<eri inits·pre-
`llcription arid patients should. be instructed against use by
`individuals other than the patiimt for· whi:5in it was pre-
`scribed, as this may have sev(lre medjcat1:onsequences .for
`that individual.
`.
`·
`· ..
`·.· · ·
`:
`~ene~ai
`.
`MS CONTJN~·is·i:i:ttended for m;e i.n patients who.'reqUir~
`ri:iore than several days: continuoi?,s. treatmep.t with a po~ent
`opio!d analgesic. The controlled:re1ease natill:e of the formu-
`la,tion:!lllo.w:s it t<J.be.aclJ:n4tj.stered .on a mo:r!l·eonvenie~t
`schedule 'than conventionitl immediate-release oral mor-
`phine products. (See CLINICAL PHARMACOLOGY:
`Pharmacokinetics arid-Metabolism~) However, MS CONTIN
`does not release morphine continuouslY over tlie course of ii
`dosing interval. The administratioil,of single doses of MS
`CONTIN on a· q12h dosing scheCJ.ule will result in higher
`peak and lower trough: pla,sma levels than. those that .occur
`when an identiCal, daily. dose ofmorphineis administered
`using~ conventional oral formhlatioils on a q4h regimen. ·The
`clinical significance o£ greater fluctuations in. morphine
`plasma level has not . been systematically evaluated, (See
`c D~SAGE AND:ADMlNISTRATION.)
`'
`Information will be. supl!rseded by supplements ;md subsequent-editions
`
`;,, · , > ~ : . · .•.. ' :.
`
`·: . ·_ · , .
`
`As with any potent opioid, it is critical to adjust the dosing
`regimen for each patient indivi.dually, taking into account
`the patient's prior analgesic treatment experience, Although
`it is clearly impossible to eniilli,~rate every consideration
`that is important to the selection of the initial dose and dos-
`ing inte.rVal of Mf?. CONTIN; attention shquld be given to 1)
`the daily dose, potency, a,nd c~ar~t;teristics of the opioid the
`patient has been taking previously (e.g:, w;hether it is a pure
`agonist or mixed agonistlantagonist),. 2) the reliability of the
`relative potency estimate used to cafculate the dose of mor-
`phine needed [N.B. potency estimates may vary with the
`route of administration]' 3) the degree of opioid tolerance, if
`any, and 4) the ge~eral cqndition and medical status of the
`pati~il~. · .
`. ·
`.
`.
`·
`Selectipn of patients ·for ·treatment 'with MS CONTIN
`should be governed by the same principles that apply to the
`use of morphine or o,ther potent opioid _analgesics; Specifi-
`caily, the.increased risks associated with its use in·the fol-
`lowing popWations s~ould be. cqnsideredi the elderly or de~
`bilit;lted and those with :severe impairment of 'hep'atic;
`pulinonarY. or renal function; iny'xedema or hypothyroidism;
`adrenoco:rti~al irisuffiCiency (e.g., Addison's Disease);· C11JS
`depression or coma,; :toxic ps;y:chosis; prosta~'Qhype~ophy;
`· or ili!jthral stricture; .~cute alcoholism; d~lirium tremens;
`k:YJ)hos·coliosis; 'or'inability to swallow,
`. ·
`·
`··
`The. administration of morphlne, like' an opioid analgesics,
`may obsc~e tl:le'·diagnosiS or clfuical course in patients With·
`acute abdominal·conditions;· ·
`· ·"
`:
`·
`Morphine may aggravate J?r.e::'existing • convulsions in pa~
`tients. witj:l conVlllsiye disorders. 'Morphine shou]d be used
`\\7ith caution ii:l p·ati~nts abOutJo uildergo surgery' ofthe bile
`iary tl,'a'Ct 's.ince it may ca_l!Se spasm of tile sphiricj;er of Oddi.
`Similarly/morphine shoilld be used with caution in patients
`With acute pancreatitis seconda:iy to biliary 'tract disease.
`lnforinatiordor Pi:ltients ·
`·
`·
`·· ·
`If clinically advisable, patients receiving MS CQNTIN
`should be given the following- ins.tructions by the physician:
`1. Appropriate pam ·management re.quifes chailgils :in the
`dose to maintain best pain controL. I>atients shogld be ad-
`vised· of the need to cont~?ft1leirpliysician ·if P.ati,l ~ontrol is
`iga9,eq~ate,hut not .. to change the dose of MS CONTIN
`without consulting th~ir physi<ei~. . .
`•
`.
`.
`·. . .
`2. Morphine may impair niental a~d/oi/physiCal ability re"
`quir.ed for the peiformanqe · pf pote!itially: hazar<!-im;-; taski;
`(e.g.,d.Jjving, operatingmachineiy:).::ga.tients·started on 1;1:8
`CON'l'IN or whose dose 4as been ;ch;mged sliouid refrain
`from dangerom;; activity'until it is established that they are
`not advers~ly a:irec~d,
`. ·'' '.''~ •. ·; ·;: :
`'
`.··.
`.
`3. Morphine should nqt be taken with alcqhol .or pthe:r,CNS
`qepressa:Q.ts (sleep aids, q;mquili~er~) .. ~ecau.s~_\l-dditive ~f­
`fectsincludhig QNS .,.depression .m.ay ·occur.· A pliJ:~id3.i;l,
`should be consulted if bther presctiption medications are
`current1)7being used or are prescBbed f~J," fg~ure -\i~e. · .
`'
`4, For women of childbearing poteritialwllb'tie'co:in:e or ,are
`plailliipgto ~ecopi~. ~r.~~?t;. a pliy~ician':s~ohl_d, b~~ cori~
`suited regarding. analgesiCs and other drug )lSe,
`·. ~ · ·
`~
`5. Upon completion o:ftherapy; it may be appropriate t<l ta-
`per thei morphi.D.e dose, rather than abruptly dis~on'tiiiuEtif
`6. While psycholoiical dependence ("addiction") tomorplllne
`used. in the treatment of pain is y~cy· rare; morphine is oi'le
`ofl)l Class ofdrugsJtiiowri to be ab'used ari,d should.'be Iiiui2
`died accordjngly,
`· ·. · .
`·
`"
`,
`·
`7. The MS CONTIN'200 'ing Tablet !sfor use.onfy m opioid~
`tOlerant patients teqUir),b.g tlaily morphine equivlilent dos-
`ages of 400 mg ~r more: SpeCial care must be taken to avo!d
`accidentai ingestion or the use by indiViduals. (inCluding
`children) other than the patient for whom it was origipally
`prescribed; iii>' such UiisuperV:ised use m~y have se'Ve:J,"Ei, even
`fat1iJ,, c:Onsequimces; .
`.
`'
`.
`Drug'lnteractions · (See. also: WARNINGS)
`The· concoriritant use' of other central nervous system de~
`pressants · includhlg sedatives or· hyPnotics, general · hlies-
`th~tics, pheiiothiaiines;-tranquilizers, and alcohol may ptoi
`dui:e additivi:!' depressant effects~' Respiratory 4epressioil,
`hypotensiori; anil profoll.nd· sedation •or· coma may occur,
`When sucli combined theri'py is: contemplated, tlie dose. of
`one or bo~ agen~s should ·be i·educed: Opioi4 anaigesksjhi-
`cludiirg MS 'CONTIN, may enhance• the'·rieuromuscufaf
`blocking actioll' of sk"eletal muscle tellixants'lkd 'prQdlice an
`increased<degree of respiratory depression.
`._,, . c.-:
`•
`Carcinogenicity /Mutagenicity /linpairme'iit of Fertility ·· ·
`Studies· of morphine sUlfate· in ·arnm:li.ld;o evaluate·th"e
`drug's carcinogenic and·'mutage:iric potential-or the effect<mi
`fertility,have not. been conducted,,.·•,·
`Pregnancy·
`...
`·.
`Teratogenic,Effects" CATEGORY C
`Adequate allimal studies on reproduction.·have not beeh
`performed to determine whethe.r~·morphilie affects fertilitY
`inc males or females. There· are rio well-controlled·studies in
`wom:en;'butmarketing experience doe!?•not:include any ev:c
`idence:ofadverse,e:ffects on the.fetus folloWing routi'he
`(short-term) .clinical• user of. morphine· sulfate products. Al"
`though there\fi:l·no dearly-defined risk, such ex;perience can~
`not exclude the-'possibility of infrequent or subtle da.)nage to
`the hU.mari fetus.
`~.. "T '"'· ·
`· ·
`· ·
`MS: CON'l'IN® '·shou;ld He used ~n pregnant. women only:
`when clearly needed, (See. also: PRECAUTION~: labor
`and.DeliV.ery, and DRUG ABUSE AND. DEPENDENCK•)
`Nbnteratogenic Effects
`.
`~-
`Infants born fron:rniothers.who have beeii takiiig morphine
`chronically may.exhibit withdrawal symptorp.s;
`,,
`labor and Delivery.,.
`' .. · ·
`MS CONTIN.is not recomi:nended·for use'in women·during
`and immediately prior to labor. Occasionally, ·opioid analge~
`
`.
`
`PHYSICIANS'.DESK REFERENCE®
`
`sics inay prolonglabor through il:c~iQJ?,S;:Which teinpotatil
`redu