RECEIVED
`NOV 2 2 2004
`LDLK&M
`
`59
`2005
`
`EDITION
`
`PHYSCANS'
`DESK
`REFERENCE®
`
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`ISBN: 1-56363-497-X
`
`KASHIV1068
`IPR of Patent No. 9,492,393
`
`

`

`404/AAI
`
`ORAMORPH® SR
`[or-a-moiil
`(MORPHINE SULFATE)
`SUSTAINED-RELEASE TABlETs-·
`15 mg, 30,mg,_ 6J);mg, 190 mg .
`:&. only.. . . . ·--.
`'.
`.
`. '•
`
`:
`" ..
`NOTE
`TIDS IS ASUSTAINED'RELEASE DOSAGE FORM:··
`·PATIENT SHOULD BE INSTRUeTED TO-SWALLOW :
`THE TABLET AS A WHOLE; THE TABLET SHOULD
`NOT BE BROKE!'l' IN HALF,- NOR SHOULD IT 13E'·
`CRUSHED OR CHEWED.' •
`.
`·
`· " "· .....
`. THE SUSTAINElTRELEASE 'OF MORPH.!NE FROM·
`ORAMORPH SR SHOULD BE TAKEN INTO CONSID~ :
`ERATION'IN EVENT OF ADVERSE=REACTIONS OR
`· OVERJ?OSAGE.~
`. .
`
`.
`
`DESCRIPTION
`Each tablet for oral ~dminiatration contains:
`Morphine sulfate ............ 15 mg, 30 mg, 60 mg, or 100 rng
`in a .. tablet that provides. for _sustained release of the
`medi~~ti.()n, · ,
`. . '_
`;. .
`.
`".
`·
`Morphine sulfate occurs as white, feathery, silky.crystals,
`cubical masses of crystals, or white crystalline powder; it is
`soluble in water and slightly soluble. in a]cohol. Morplline
`has a pKa of 7.9, with an octanol/water partition coefficient
`of 1.42 at pH 7.4. At this pH, the tertiary amino group is
`mostly ionized, making Jhe molecule water-soluble.
`Morphine is signif!~;antly more water-soluble than any other
`opioid in clinical use:
`.
`Chemically, morphine sulfate is '7,8-didehydro-4,5a-ep()xy-
`17-methyl-morphinian-3;6a-diol sulfate (2:1)(salt) pentahy-
`drate, and has the following structural formula: ·
`
`Each ORAMORPHSRTablet contains 15 mg; 30 mg, 60mg,
`·or 100 mg Morphine Sulfate USP. Inactive ingredients: Lac"
`tose, Hydroxypropyl Methylcellulose; Collofdai Silicon Dioi-
`ide; aD.dStearicAcid.
`·
`,9LINIC~ J:lHARMACOLOGY
`Morphine is the proto~ype of many narcotic drhgs that in-
`teract predominantly wit4 .. the opioid _11-r~<;eptor. ~hese
`JI-binding sites are discretely distr~butesl in .the human
`b_rain, .with·high densities in the posterim; amygdala,_hypo-
`thalapms,, tl:lalamus, nucleus caudatus, putamen, 1'.\lld cer-
`tain cortical areas. They are· also.fomi,(l on the terminal-ax-
`on,s ofpril).lary affer;ents.:Within Ianiinaei and II (substan.tia
`gelatinosa),of the spinal-cord and in th~ spinal nucleus of
`'the trigeminal_.I).erve.
`.
`. . . , ·.
`..
`,
`. · :
`.
`In clinical settings, morphine exer.~ its principal ph~a­
`cological·effect on the central nervqus system and gastroin- '
`~stt11!!1. tract. Its primary actions of therapeuti!; value. _ll.l'e
`analgesia and sedation.: Mofll4ine appears t() increas~ the
`patient's to~erance .for paip. and to. _4ecreas,e discomfort, .al-
`tlwugh thE~ :'presence of ~he pain~ itself may still 'Qe recog"
`nized, In aqclition to-analgesia·, _alterations in Jl100d, eupho-
`ria and dysphoria, ·and drowsin~ss co~only occur. . .
`.
`Morphine :depres~flS vario-gs·,:respiratory centers, depres.ses
`the. coug}l refiel'~ and constricts the pupils. Analgesically,_ef-
`fective blood, levels of morphine may cause nausea and vom-
`iting directly by. Stlp,lulating ·~he' ci:J,ep,lOr(lC~ptor trig~er
`
`zone, but- nausea ~d vomiting ara significantly more. com-
`ma~ ffi. ·ambulatozy'th!!ll in recumbent patients; as is pns-
`tural.;syncope;" · .. . : ; · · ':: "'·
`· · · --
`Morphine iricreases-the'.tone and .decreases ,the propulsive
`contractions··of the sm:ooth .muscle of. the gastrointestinal
`tract. The resultant prolongatiQri in gastrointestinal transit
`tilpe .is. responsible ·for ·the .constipating ·effect. of morphine.
`Because morphine may increase biliary-traat pressure, '
`soine~patients With bilii,U'y coliu<may experience wors!'!ning
`;rathedhliiNelief of pain.
`·
`While morphirie. generilly increas~s.-the 'tone of·urinary-
`·tract· smooth muscle,. the-. net effect tends to:.be variable~ in
`· some cases. producing urinary urgency, in. others; difficultY
`in urination.' . ,
`. .
`,·
`.
`.
`.
`. ..
`In thl'!rapeutic doses, m.orph,ip,e,qoesnot _usually exert ¥1ajor
`effects on the cardiovascular system: SQJlle .patients; :how-
`eyer, exhibjt a prope_l,lsity.togev\'!~Op orthostatic hypqj;enf?i()n
`.and ·f~ting. Rapid wtraven,pu~· 4ljectiOJ1 is ~Or\'! lik~ly. to
`precipit~te a fall in~ bloogo~~rllssure than: oral dol;l_ing ... , : .
`Mqrphine can.cause ):ri.st;,u;nine release,. whiGh appears to be
`responsiblE'!· for. dilation of c~tlilleous blood :v.,es!lels; with
`resulting, fl~shing of the face and neck, pruritus, and
`sweating.
`PHARMACOKINETICS
`·ORAMORPHSIVfablets ate a sustained release oral dosage
`form of morphine sulfate. Only about '40% of the adminis-
`tered dose reaches the central·eompartniei\t because offirst~
`·pass.effect'(i.e.,.metabolisndp, the gut :Wall and liver). Once
`absorbed,: morphine. is"distributecFto skeletal,muscle, kid-
`neys, liver, · intestimii· tract, lungs, .. spleen· and br!'!,in.
`Morphine ·a]so·.cros'ses·the· 'placental membrane and has
`been found·. in breast rriilk. · · . : ·· · >
`For an practical purposes, virt~ally all morphine is con-
`verted to glucuronide metabolites;· only a small fraction (le·ss
`than 5%) of,absorbed morphine is demethylated. Among
`these· glucuronide metabolites, morphine"3"glucuronideAs
`present in the highest:p]asma conc(mtration,following.oral
`,a!ll;rtinistration; a sml!ller fractiol). is cop,verte<Lto.m,orphine"
`6~glucuronide,:.whicllJ:ws the greater.~algesi<; activjty o.f
`these two metaiJoli~s:. ,
`. , . ·
`.
`· : .
`·
`The glucp.r9.nide system hilS a high capacity and is. not eas-
`ilj saturated;· even in disease-: Therefore,. the rate of d,elivery
`of morphine to ti:J,e gut al).d liver does not influence the total
`and/or the relative quantities of the various ~~etabolite!l
`forme4:
`· .. .
`.
`,
`··.
`,
`.
`.
`. · ..
`.
`.·. ·
`,'J1le ph~macokiitetic paraml'!ters following oral aqministrll-
`tion-of ORAMORPH SR, presentE)(i in the ta~le b_elow, show
`considerable inter-subject variation, but are representative
`of average values reported in the literatlfl'e. The volume of
`distribution (Vd) for 1norphine .is 4liters per kilogram
`(Ukg), and the terminal elimination .. half-li(e is appro~-
`mately ,2 to. 4 hour1;1.
`··
`· · ·.
`[See_ t'able below I
`. ,.
`.
`.
`.
`. .
`c.
`__
`FolloWjng. the adJllinistration of conventional, immediate-
`releaf:le, oral morphine prod\tcts, 'approximately 50% of the
`morp:Illne, that Will ever: reach tP,e. central compartment,
`re,a!!hes it within 30 minutes. 'Following the administra,tion
`of an equal amount of ORAMORPH SR to normal voluri.-
`teers, however, 50% ofabsorption occurs; onaverage; after
`1.5 honrs.'
`· · ~
`·
`'
`·
`· · ·
`·
`A phar:inacokinetic ·study in normai volimteers indicates
`that'there is little to ~6 effect-on 'the syste!nic bioavailaoility
`of ORAMORPH SR when admiriistered Witn food.
`Although vru:iai::ion ih the physico-niechamcill properli.es of .
`a_forill~ation of an.:or~l morphine drug product cab. aff~<;t
`both' its:'absolute' bioavailability and its absorption rate con-
`stant (ka), molphine distribution and cl~arance are un~
`changed,'as'they ate fuiidamentaJproperties ofmorphllie in
`the·'organ~sm. However, in chronic use, the possibility of
`shifts·' hr metaholite-t6:parent drug ratios cannot· be
`· _, ..
`excluded.
`When:inimediate-releasEf'otal morphine or ORAMORPHSR
`is 'given ori a fixed dosing regimen, steady-state is achieved
`in about one to two days~
`
`TABLE OF APPROXIMATE1- AVERAGE PHARMAcoi<ll\tETIC
`PARAMETERS FOLLOWING ORAL DOSiNG OF ORAMORPH SA,
`
`Bitiavailability .
`(oral compared to injectable)
`·. 'Iilean '(ra~g~) · ·
`,- ... '
`.
`
`iime-to~peak:plasma
`concentratioii{T nia~l (h) ·.
`
`Peale plasma concentration mean (range)
`{Cmaxl (ng!mL) [single dose]-' -
`
`mean. ·
`
`Volume of
`distribution(calc11lated from·
`mean clearance and
`· · ·
`terminal half-life) {Vd(B)}
`(I.Jkg)
`
`~ .. 7 (1-6)
`
`3.8 (~-7) ;
`
`•11.1 (6.5-16!2)
`
`9.9 (5.0-18.())
`
`16.1(10.0-25.3)
`
`27.4 (14.1-46.1)
`
`;\;_-.
`
`................................ , .............. '4 L/kg
`
`. Dose inet~bollzed = appro~ately 90%
`• · :
`·Morphine rrietaboli.tell (%) = i:Jiqi·phifie-3-'giucutonide (55-75%), morphine-(>-glucuronfde (1"5%)
`
`1D.erived from pharD+acokinetic studies in 24normai volunteers
`
`Information will be superseded by ,supplements· a11d subsequent eqitions
`
`: PHYSICIANS' DESK-REFERENCE®
`
`For a given· dose and .. dosing mterval; the Aiea"Under~the­
`Curve (AUC) and average blood concentration of morphine
`at steady-state (Css).will he•indepenaent of.the_type:•oforai
`formulation iulniinistered; as long·as:the formulations have
`the sani.e ~absolute bioavailaoility. The absorption. rate of a
`formulation .will, however, affect the max:im,um ( Cmax)~and
`minimum ·:(Cmi.D:) plasma concentrations-rand the· time ,be~
`tween:.ad.:ministration·.and •their.:occurrence,. For any fixed
`dose and-dosing interva,l; ORAMORPH' SR,wilhhave, -at
`steady-state, a lower Cmax and a higher Cmin'thari·conven~
`tional·immediate-release•morphine;.which might be ather:
`apeutic advantage in chronic pain controHsee also· PHAR~
`MACODYNAMICS) .. ·.'· .'' •;·
`.
`. .. ·. · .... ,
`·.• .··.
`The clear~ce of morpliirie OCCUrS prtinaruy as reniil excr¢"-
`tion of'mori)hine~3-glucuronide. A ~mall amoi.mt ofthe glu~.­
`uhinide conjugate is excreted in the'bile, and there'is'soiiie
`minor enterQliepatic recycling; about 10% ofthe ghicuronjde
`conjugate is excreted iii the' feces. :Because morphine is es-
`s'entiallymetabolized hi tlie liver, the effects ofreniil disE~ase
`on morphine's clearance axe not likely to be pronoiinced. As
`with a'ny drUg; however, caution should be taken to guard
`'against unantiCipated accumUJati011 ifrerial andforlieP,atic
`. .
`:.'·'
`·:fuiiction is senously i.iilphlred.·•'
`PHARMACODYNAMiCS
`.
`.. .
`.
`In cpnical settings, morphine's primary actions ofthl'!:r:apeii~
`tic 'value' arE~ anMgesla-and sedation. Opiiite. analgesia in~
`volves at Iea8t three anatomical areasbf the' central neTiiotis
`system: the periaquedil.ctaloperiventricUiar gray ,matter, the
`ventromedial medulla, ~4. the. sp~~- cord, .. Morphine ap-
`pear~ to iD.crease the p;itient's tOierance for pain;-and to de-
`cre~se ~the. discomforl, although the presence of pain itself
`may still pe recogrii~ed.
`.
`.
`... . . .
`. .
`.
`.
`Whjle. there is co,n,sid~r~iible vs,r,iabil.i,tyin 'the. relationship
`between morphine blood' concentration and analgesic re-
`sponse, effllcti:ve_ a'nalges~a probably will. not _occur below
`some miriimum blo'od l~vel in~ given ·patien't. The minimum
`effective blood ievel for ai:t;Jge,Sia ~ill vary ak~ng ·patients,
`especially among patients .Who have been pr~Viotsly tre'ated
`with potent JI-agonist opioids: Simiiarly, ther,e is consider-
`. abie, _vari~bility in ·the rehi.~ionsliip h'etweeJ?. .ll1orphine
`plasma concentration and untoward clinic1ll. resp(;lnses,_ but
`higher C()ncentratiO~S are Illore likely to be toxic.. . . ". ,· ' .
`In contrast to immediate_-releas.e morphine, after dosing
`with ORAMORPH SR; the ·morphine· blood levels show re-
`duced fluctuation betWeen p_eak and.trough plasma levels;
`that means that they are more ceritei:ed Withiri the theoret-
`ical'therapeutic window'. On the other hand', the reduced
`fluctuation in . morphine plasma· concentration mii# cor1-
`ceivably affect other phenome~a. as for example; the rate of
`tolerance induction.'
`.
`·
`.
`· ·
`,_.
`biiAMbRPH SR is an. analges~c .intended for patie,nts who
`require chronic morphine analgesia and \vho will· have; in
`consequenc~. markedly' different degrees of pharmacody-
`namic tOlerance foi: ~pio!d drugs. Mor,Phine~and silnil3! opi-
`oias induce tOlerance to their effects, so that a shortening 9f
`the duration of satisfactory analgesia may be the·first sign
`of an increase in tolerance.
`'
`· ·
`once. patients are started on· morphine, the dose required
`for satisfactory analgesia will rise, with the rate of develop-
`ment Of to]Eml~Ce ·varying; depending on the patient's prior
`narcotic use, ·fevel of pain,' degtee of anxiety, use of other
`CNS"active drugs, cii,'culatory status, total daily dose, and
`'the dosing intervaL · ·
`.
`· · "·'
`· .
`· • ·
`INDICATIONS AND USAGE
`ORAMORPH • SR is indicated· for the relief. ofpain'in pac
`tients.-who· require'opioid analgesics for more than-a few
`days.
`'
`. . .
`.
`coNl.'R.AnWICATlONS
`~::m.AMORPH SR.is -co11train;u!!at.e{ in pa.tients. with respi-
`ratory deiJt!J,S,Si(Jn ii'\the abseneeofresuseita#ve equipment,
`in patieiJ,tf:l,with acute or severe broi).chiai asthma al).d in
`patie,nts with known hypersensitiVity to morphine.
`OR.AMOI{.PH SR is contraindicated in any patient wh9 has
`or is susp.ef!ted of havi~g .a paralytic ileus.
`· ·
`WARNINGS'
`IMPAIRED RESPIRATION:
`Respiratory depression is: the 'chief hazard of all morphine
`·preparations. Respiratory depression pccur's more :fre-
`. quently in the elderly and debilitated patients, as well as in
`those ·suffering from: conditionS accompanied-by·hypoxia or
`hypercapnia when·· even moderate therapeutic doses may
`dangerously decrease pulm<inary 'ventilation:
`Morphine should be ·used with extreme caution in patients
`who -have a decreased respiratory reserVe (e.g.,_ emphysema,
`severe obesity, kyphoscoliosis, or paralysis of the phrenic
`I).eive). ORAMORPH SR should not -be given in cases of
`chronic. asthma;. upper airway ob~tructioh, or in an:y other
`chronic pulmonary disorder without' due consideration of
`the known risk of acute respiratory failure following mor-
`phine •administration in.such· patients,
`DRUG ABUSE AND DEPENDENCE
`.
`SUBSTANCE:.
`Morphine sulfate is a SchedUle Uiiarcotic under the United
`States Controlled Substance Act (21 U.S.C. 801-886). ·
`Morphine is tlie m6st:cominonly cited prototype for narcotic
`substrutces that· possess< an addiction-forming or addiction-
`sustaining liability.: A patient may be at risk for developing
`a dependencii to morphine if used unproperly or for overly
`long periods of time. As with all potent opioids which are
`Ji"agonists;. tolerance ·as W'ell as psychological and physical
`dependence to: morphine may· develop irrespective of the
`route of administration (o'rai, intravenous, intramuscular,
`
`- CONTROLLED
`
`KASHIV1068
`IPR of Patent No. 9,492,393
`
`

`

`pRODUCPINFORMATION . '
`
`•
`
`•
`
`_,_
`
`••
`
`•
`
`-
`
`intrathecal, or epidural). Individuals with a prior hist9,ry.of
`opioid'or other substance aouse o'r'depimdence; be~~ in?re
`apt to respond to ·eupho~~ge¥c ~d reinforcin~ PFg.P.~f!:ieS. ·of
`·.
`morphine, would be cq~1d,ere.(l tqbe (it_gre~t-~r::ps~ .. :_
`Care must -be taken to. avert Withdrawal ·sympt<!ms. whe~
`morphine is discontinued abruptly ·cir ):iPO.il adininistfati.on
`of a narcotic antagonist. ·
`· · -
`· ·
`- - · -
`pRECAUTIONS
`-:
`..
`.
`Gent?rai_Pr~cautions: ·
`Selection of patients for trea,tm\)n~ with ORAMORPH SR
`should be goverp,ed by.tJ!«:! same principles that apply_~o the
`use ofmorph_ine ~~other-potent opioid analgesics. Narc<ij;ic
`analgesics are drugs th!lt have a nru;row: th~r.apeu,t;i,c .ir\de~
`in the old, the sick, and the infirm, i.e., the very populati(!n
`in ·which their use is mdicateq. Phy~ici~s ~h5J1Jld,ipdivi~11-
`alize treatinent withJ)Rl\¥QRPH ::?:fl. in EJV~ry plS\l, f",eig4~
`ing the need for. analgesia· against _th~_ risks of se~ou~ 0~ fa~
`tal reactions t9 tl;te drug.
`. .
`.,.
`. 7
`Use in Patients with Increased lritracraniaiPressu,re,_gf1~it!!
`Head: Injury:
`·
`.. · . · ··
`b:RAMORPH.SR should be used with extreme caut#in.iil
`patients With in~reased intracranial pieiist#'~~?r wi~~ h~.~d
`injury. The resprratory depressant ~ffects,9f.morphine (~Il7
`creased pC02) may result in elevation of cerebrospinal :fl.l:iid
`pressure and· niay thus be markedly exaggerated in Jhe
`presence of head injury, other intracranial lesions, or a:pre-
`existing increased intracranial pressuhi~ · Morphine . pt9r
`duces effet:ts y.r~clJ. JiiliY ob~eure·J.\e.1lrol~gi_c ,signs of ~~e,r
`increases ·in: pressure :in: patients· with head ip.juries:
`Pupillary changes (nuosis), assodatea #~li 1llom~Ei, '¥iay
`conceal the existence, extent, and course of intracranial
`· '. · · '·}:- _;-:,i:-: : ··: : ' :· ic : ·
`paflioiog)r; ·· ·
`· ~ ;
`· :
`Use-in Hepatic ot Renal Disease:· ·
`.
`Tiie clearance of morphine :rtiay: be reduced in patients_ with
`hepatic dysfunction, while the clearance of its metapoll.tl~s
`niay be decreased in renal dysfunction. This will be mani~
`f~sted by both a prolonged elinlination half-life ~¢d the a~­
`c;rnulation of_levels of either morphine or its metabolites in
`excess of those produced in normals, ·With the potential foi:
`an :hicrease of adverse effects (see WARNiN~E? 'and AD-
`VERSE REACTIONS). These changes in m.oriJ)iiile pharma-
`codynamics, in patients with hepatic or renal dysfunctions,
`should be considered when adjusting the dose and dosage
`. interv:3Js;taking also :irito account the·slowcrelease charac-
`ter of ORAMORPH SR.
`· .
`'i:Jrug Interactions:
`.
`. _
`._ _ _ .
`Use with Other Central Nervo!ls8ystem Depressa'n:ts: . ',; ',
`The. depr~s~ant effects . of 'morphilie ·are potentiated' by)he
`presence 9f other ·eNS depressants_ such as alcohol, seda-
`tiv~~. rui#h;istaminics, or psychotropic drugs. Use of:neurp-
`leptics in' conjunction with oral mor!>hine·may'incre-~se,t~e
`risk of respiratory depression, hypot~nsion iffid proforin_d se~
`dation.or coma.
`·:
`Interaction with Mixed Agonist I Antagonist Opioid A,nal/ie-
`sics:
`,., _,._
`' _ .. · ...
`·
`Agonist/anta&'oilist analgesics (i.e., pentazocine-, · nalou~
`phine, butor]Jhanol, or buprenorphipe) sho~c,t~QT· be_ a4-
`ministered to patients who hav~ received or ~~-receiving'_a..
`course of therapy with a pure opioid agonist analgesic. In
`these patients, the·Iilixed agonist/antagonist may alt~rt4~
`analgesic effect or may precipitate withdrawaLsyinptoins;-,
`Carcinogenesis, Mutagenesis, lmpairrrituit of Ferti/ftyi
`. : .
`Studies of morphine sulfate in animals to evaluate the
`drug's carcinogenic and mutagenic potential or the effect on
`fertility have·not been conducted.
`·
`·
`·
`Pregnancy:
`Teratogenic Effects - C~tegory C: There are no well-
`controlled studies in women, but marketing experience does
`riot include any. evidence of adverse effects on the. fetus fol-
`lowing routiile (shortcterm) clinical use of morphirie ·sulfate
`pr,oducts. Although there is no clearly defined·: risk, ·such
`eltperifi)n.~e. cannot exclude the possibility of infrequent or
`subtle: damage to·_ the human fetus.·
`. _
`:. · _ ·_
`· ORAMOR,I>H SR should be. used in pregnant woniertonly
`when clearly .. needed. (See also: PRECAUTIONS: -Labor ;ma
`Delive:rY, ~d DRUG ABUSE AND DEPENDENCE·CON-
`..
`TROLLED SUBSTANCE.)
`.
`-
`Nonteratogeilic Effects:
`Infants born from mothers who have been taking morphine
`chronically may exhibit withdrawal symptoms:
`·
`-
`. -
`Labor and Delivery:
`ORAMORPH SR is not recommended for.use in women du:r"
`ing and inrmediately prior to labor. Occasionally, opioiq an-
`algesics may prolong labor through actions whic~tem'p!Jiilr~
`ily reduce the ·strength, duration and frequency of uterin'e
`contractions.
`Neonates; whose mothers rece~ved opioid analgesics during
`lab9r, shoUld be observed closely for signs of re~piratory de-
`pression, _A specific_ nilfcotic aiitagoriist, naloxo~e, l!hotlld be
`.availab1e for reversal of 'narcotic-induced. respiratoii. de~
`pres1;ion ih the neonate.
`·
`·
`-..
`Nursing Mothers:
`·
`ORAMORPH SR should not he given to nursing mothers be-
`cause morphine is excreted in maternal milk. Effects on the
`nursing infant are not known, but withdrawal symptoiD:S
`can occur in breast-fed mfants when maternal administra-
`·
`tion of morpliirte sulfate is stopped.
`Pediatric Use:
`ORAMORPH SR has .not been ey;lluated in childrem. Its Ul?~
`in the pediatric population is, tl).~refore, n()t reeommended.
`Use in the Ag~d: ·
`·
`The pl;larmacodynamic effects of morphine in the aged· are
`more variable than in the younger population. Patients will
`
`c
`
`· -· ·
`
`.
`
`:• •
`
`'
`
`'' ,. __
`
`· •• ·
`
`vary widely in the effective initial dose; rate ofdevel9pment
`of tolerance, and the frequency andoimignitude of as!!ocfate·d
`adverse effects as the .dose is increased. Individualization· of
`doses must receive careful· attention in elderly patiei).ts;
`Information for Patients:
`If clinically advisable} patients reciliVing :oRAMORPH SR
`brand of morphine sulfate sustained release tablEitsrshould
`be given the followingJnstructions by· the physician: · · '' ·
`1. Morphine may produc~ psychological and/orphysical.'ife-
`pendence, For this reason, the dose of the drug slioUliinilt
`··be increased without consulting a ·physician. · ·. · · : · · ·
`2. Morphine may impair mental.andlor phy_si_cal ~bility re-
`quired for the peiforinaiice of potentially hazardous ta:skS
`(e.g., driving, operating machiD.er)i). · ·: · ·' · · · - ·
`·-
`' · ~ _
`3. Morphine sli(lllld iigt he t!lken'Wip}l :alcohol or. other CNS
`depr~§san:ts (sleep 'aids, tranquilizers} because -additive
`. effects, mcludilig' CNSdepression, m'ay occur. A physi~i~
`. should: be ·consulted if other pres~nption and/or over-tlj'e~
`counter m:edi<;~tions are Currently· being· used Or' are pre.-
`scnhed for futurE) use.
`. . '
`' "' ' .
`. ... . .
`'
`'
`.
`1:: For wo:riien ofchlldoeating'}iotllntial;~wl!il beco!Ile o~ liie
`·_ .j:llaJ,Jirin'g to become pte~ant, a·phys!ciaii should bti'ctih~
`-
`,: ,~s~~ed~_r~.g~ding an~gesics _and' o.tli~i-~g\~~6.
`ADVERSE:u.EACTIONS
`
`NOTE: THE SUSTAINED RELEASE OF MORPHINE·-
`FROM ORAMORPH SR SHOULD BE TAKEN INTO
`CONSIDERATION IN THE EVENT OF OCCURRING
`ADVERSE REACTIONS.
`
`Adverse reactions_.caused by mor.pl;rine_ ~re ess.ep.tiallythose,
`observed with other opioid analget?ics: ',I'he_y, hiclude the
`following major hazards: respiratory depression, and less
`frequently, circulatory depression, apnea, shock and car-
`diac arrest secondary to respiratory and/or circulatory de-
`.pression.
`' · · ·. · · .. '
`·
`Most Frequently Observed Reactions:
`Constipation, nausea, vomiting, lightheadedness, <li,?;ziness,
`sedation, dysphoria, euphoria, and sweating .. Some of these
`effects seem to be more prominent in ambulatory_patients
`and in those not experiencin,g se_yere pain. Some aslverse re-
`actions in ambulatory patients may be alleviated if-the pa7
`tient is in a supine position.
`_ .
`.
`Less Frequently Observed Reac;tions:
`Body as a Whole: Edem.a, antidiuretic effect, chills', inuscle
`tremor, muscle rigidity.
`·
`·
`Cardiovascular: Flushing of the face, tachycardia;· b:rady-
`cardia, palpitation, faintness, syncope, . hypbten:sion,
`hypertension.
`·
`Gastrointestinal: Dry mouth, biliary tract spasm, laryngo-
`spas~, anorexia, diarrhea, cramps, :ta~te alterations~. c · ·
`Genitour{nary: .. _ Urine retention or hesitance, reduced li-
`bido an:d/or potency.
`·
`·
`'
`Nervod$ Syste~~: Weakness; 'headache,'' agitation,' tfe!llor,
`un:cooi:di!!ated muscle movements; seizure; paresthesia, al-
`terations of mood (nervousness, apprehension; •depression;
`floating feelings), dreams, transient hallucination ana ~s­
`o'rientation, visual disturbances, insomnia, increased' intiac
`·__ _ · . · . -
`·:
`·
`cranial pressu.re.
`- . · ·
`- . . :
`. $kin: .Prurltus; urticaria and othei· skin 'r~shes.
`-~pecial Senses: 'Biurred ·vision, nystagmus,' d~piopia,
`miosis.
`- -,.c
`DRUG ABUSE AND DEPENDENCE
`Opioid analgesics rriay cause psychological an.d physi~~ de-
`pendence (see WARNINGS). J:>hysicai dependence}'es~tsin
`Vlithdrawal symptoms in patients.wh() abruptly discontinu~
`the cirug; or these syniptoms may be pre.Gipit,(!ted ~ou,gh
`the adininistration of drugs with al).tagonistic ·activity, e_.g.,
`naloxone or mixed agomst/antagdnist ruwlgesics. (penta?)O-
`cine, etc.; see also OVERDOSAGE). PhysiCal d~pen<l.en,ce
`us_ually does not occur, to a clinically significant degree, ~­
`til several_ weeks of co:d.tinued opioid usage. Toleranc~. in
`which increasmgly larger' doses are required to produce the
`same degree of analgesia, is initially manifes~ed by a sh9rl-
`ened' duration of anaiges!c ·effect and, §lubsequen~ly, by de-
`cr~ases in the intensity of analgesia.. )n piit1ents with
`chronic_.pain, as well as in opioid-tolerant cancer patients,
`the adniinistration. of OR.AMO!tPH SR (morphipe sUlfate)
`should be guided by the degree_ of tqlerance niamfest~d.
`Physical dependence, per se, is not ordinarily a con,cern
`w)l.en one is dealing with opioid-tolerant patients:whose
`pam and suffering is assoCiated witJian irreversil;>le il}nes_s.
`If ORAMORPH SR is abruptly WSC\J!ltinued, an abstinence
`syndrome may occur, Withdraw!ll. symptoms, inpatients _d~­
`penqent on JllOrphine, begin~ .shortly before the time of the
`next scheduled dose;,reaching-a peak_at 36 to 72 hours.a,fte;r
`the last dose, and then slowly subside over !:! period of 7,to
`10;d_ays_. Symptoms_ in~lude yawning, sweating, lacrim!ltiO).l,
`rhinorrhea, restless sl~ep,_ dil~!-ted pupils, go\)s~flesh, irrita.-
`-
`bility, tremor, nausea, yomiting, a:nd diarrhea.
`Treatment ofthe.abstinen:ce syndrome is primarily sympto-
`matic._and supportive, including maintenance ofproper:fluid
`and electrolyte balance. If withdrawal has inadvert~ntly
`been .precipitated in a patient who requires narcotics for
`pain management, the withdrawal syndrome. can he termic
`nated rapidly by the adininistrat!on.-of:a.n appropriate dose
`of-·a pure agonist opioid, such as morphine. The degree .·of
`physical dependence of a patient on:ORAMORPH SR can be
`intentionally reduced by. a gradual :red1,1ction of dosage and
`symptomatic treatment of withdrawal symptomatology.
`
`AAI/405
`
`OVERDOSAGE
`
`NOTE:- THE SUSTAINED RELEASE OF MORPHINE'
`-FROM-oRAMORPH SR SHOULD BE TAKEN INTO
`CONSIDERATION IN THE EVENT·OFAN'OVER0:0
`·:DOSAGE). " '.
`.
`.
`. . '
`..
`
`Ove~dos~ge of'k01]ihin.e is 6ii;aderize'd by respimtocy de-
`.p~-ession, with .oi:, ~jthout concoxrdtant QNS depre~sion.
`S~ce respii:a~ozy;arrest may result eitheqhrough gi~ect
`d!'!Pr~ssion of the respirlltqry ~e~t~r; or as. the result.of
`hypqxil!-, primary attention sQ.ould. be giyen to the ,esta}'ilis}l-
`ment of adequa,te-respiratory exchange through provision:_of
`a patent airway: and institution:.of.assisted;'<ir contro)led,
`veritilatiori. The narcotic antagonist, naloxone, is li specific
`antidote~ An hiitial dose o£0.4 to 2 ·mg of naloxone shoultl he
`al:lriliiristered' intravenoii~ly, simultaneously' with 'respir&~
`tory ·:r~sll.scitatiini.~ If th«;!'' desired de~ee 'of coun:t,~riliitiori
`afid--improvement in respiratory -.f'unc'tiim' is' no'f pbtirirle~,
`na1oxone may be r.epe~teq at 2'_tii~.+u~ii.iilte!-"8ls:·~"!f.ri9
`response is obsei'Ved after 10 mg'ofnalo?'l>n~has.:been'ad:
`'ministered, the diagnosis ofiiarcotic~iilduc~d, o~~~~hiai
`narcotic-induced, toxicity shqulP, b{questio~ed, Jntram~~:
`cUiar 9r subcuta:n~mis a~stration m!lji be ~~~d.if tli~ i}i-
`travenous route is not av~ilable.
`. .
`.
`.
`~ . .
`.
`As t'l),e duration of e!f.~ct of nalo)!:qne tiS con§li!Ierably §h!J,rter
`than that of ORAMORPH SR, rep~ated,ad:!ninistrati!in. -in&-Y
`be necessary.:Patients ·should b.e closely·.observed for:evic
`. d~nce -of renarcotization.
`.
`
`,-
`\NOTE: -In a ·individua! physically dependent on op~"
`. oids, .. adininistration.ofthe usual dose of.the'antagonist.
`will precipitate an acute withdrawal syndrome. The se-"
`·verity of the withdrawal syndrome 'ptodtii:\jd .. Will:de- •
`pend mi the degree of physical dependeii<!e find tne· aose
`of thianfagcinist administered. U:se -b{a 'Ii~r~ilti~'a.Iitag­
`miist in such a person shoUld ])e av<iided:Ifnecessary to
`treat seriouS :respiratory dep~ession in. a phy~iciillY d~­
`pendent patient, 'the antagonist shoUld be a~~t~!-lla
`with ext;:rep1e, ~lire . and by tit).'ation. wit4 sinhlle~- than
`.:;~~lfa1 dos~s~ of the ahfago~ist .... · ·:. • .
`. •;
`. ' .
`Wb~n:- ~ilicated-,: .iut: decontrifumati~~ sh~uld: be~~~rfo~ed
`via emesisoandfor activated:cl:iarcoal (60:to 100 gin aduits, i
`to 2 g/kg in ·children) with cathartic . .Since ORAMORPH SR
`is a sustained release product; absorptiqn may be expected
`to coiitiliue 'for riiariy• liou:r~,- pfu.ti:cW:arl:{folloWmg ari·ov~r­
`dose,·_'combined with 'deci~a~ed'peristaltic ·actiyity of-th~
`gastrointestm)H tract.
`. ·
`_ ,.
`· - __ · ·
`. .
`, • ·
`Supportive' jneas'ures . (including: oxygen,. vasopr'essors)
`should b~ _eAI~loy~d in}he }n~agm;nent of c!rcul!lt?i.y's}lock
`and pulnio~-aij ed!lmil accol)lp~yilig overdos_e as inc:licated:
`Cardiac ariest o-r' arrhytbln).as may require Cfl!diac ni~ssage
`or defibrillatio~. -
`. .
`-
`.
`. .. ·-
`.
`~
`DOSAGE AND ADMINISTRATION
`(S~e also: btiNICAL"PHA:itrvlACOJ;,Q~Y,_wA.IlliiN!JS ant].
`PRECAUTIONS .sections.)
`. _ ._
`. _· .
`. .
`• .
`. ... _ .. "
`N(:>TE:-: OR~II(lpRP8' ~{!_ rA~LEj MUST ~.E. ~'{VAL~qW~D
`WHOLE. DO,~NOJ BB~AK TliE 1ABLET. IN l_:lj:\LI:, [)Q-I'JQT
`CRUSH OR CHEW. TAKING BROKEN, ,.CHEWED OR'
`cRUS!-f~o.r~s!.:Ers c;ouLD LE~D :ro, THE .R-APID RELEASE
`AND ABSORPT)ON ,OF A