, ..
`
`;.·,.;
`
`EDITION
`
`1996
`
`Goonv:mr
`v:u\, PROCTER & He
`·
`L!BRJt~y
`EXCHANGE PLA
`BOSTON
`CE
`I MA 02~09
`
`PHYS CANS'
`DESK
`REFERENCE
`
`.
`.
`Medical Consultant
`Ronald Atky, MD, Charles S. Davidson Professor of Medicine and Master, Francis Werd PeabQdy Soclety, Har:vard Medlcat' Sc~ool
`
`President and Chief Operating Officer, Drug Information Services Group: Thomas F. Rice·
`V1ce PreSldent of Production: Steven R. Andreazza
`Director of Product Management: Stephen B. Greenberg
`"Associate Product Managers: Cy s. Caine, Howard N. Kanter _ Manager,.Database Administration: Lynne Handle.r
`National Sales Manager: James R. Pantaleo
`Cont racts and Support Services Director: Marjorie A. Duffy
`Director of Production: Carrie Wllilams
`Senior Account man.ager: Michael S. Sarajlan
`Account Managers
`Production Managers: Kimberly Hiller-Vivas, Tara L. Walsh ·
`Dlkran N. Barsamian
`Production' Coordinators: Arny B. Douma, Dawn B. McCall
`Format l;dltors: Gregory J. Westley, Edna v. Berger
`. Donald V. Bruccoleri
`Lawrence c. Keary
`·
`•
`Jeffrey M. Keller
`Index Editor. Jeffre)l Schaefer
`P. Anthony Pinsonault
`Art Associate: Joan. K. Akerllnd
`Anthony Sorce
`Director of Corporate Communications: Gregory J. Thomas
`' . Trade Sales Manager: Robin B. Bartlett
`Electronic Publlshtng Coordinator: Joanne M. Pearson
`Trade Sales Account Executive: Bill Gaffney
`Electronic Publ\shlng Designer: Kevin J. Leckner
`Dl~ct Marketing Manager: Robert w. Chapman
`Art Director: Richard A. Weinstock.
`Digital Photography; Shawn w. Cahlll, Frank J. McElroy., 111
`Marketing Communications Manager: Maryann MalorgJo ·
`Director, Clrcula~lon Be Fulflllment: Marianne C.larke
`Director, Professlonal Support Services: Mukesh Mehta, RPh
`One Information Specialists: Thomas Aemlng, RPh, Marion Gr.ft, RPh
`Product Ful~llment Manager: St!)phen SchW~ikhart
`Editor, Speclal Projects: David W. Sitton
`... .
`
`'·
`
`· .. -~ Copyright Cl> 1996 and published by Medical Ecooomics.Company'at Montvaie, NJ 07645-1742. All rig)\ts reserved. None of the content of this publlca(cid:173)
`• • tlon may be (eproduced, stored In a retrleyal system1, resold, redistributed, or transmitted In apy form or by llny means (electronic, mechanical, photo-
`copying, recording, or otherwise} wtufout the prior written permission ot the publisher. PHYSICIANS' DESK REFERENCEe, POile, PDR For Nonprescription
`.
`Drug~. PDR For Ophthalmolo~, Pocket POil$, and The PO~ Famlly. Gulde to Prescription OnJg&e ere reglstered trademarks used herein under license. PDR~
`·Generl<;stM, POR Gulde to Drug lnteractioris• Side Effects•lndlcatlons"', The POile Family Gulde to Women's.Health and.Presi:tlptlon Drugs"', The PD~ Family
`.. Guide to Nutrition and Health™, PDR4D Electronic library'"'• PDR4D Drug Interactions, Side Effects, Indications Diskettes"', en,d PDRGD Drug REAX™ are trademarks
`. .
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`used herein under license.
`· :
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`Ofllcers of Medical Economics: President and Chief Executive Officer: Norman R. Snesll: President and Chief Operating Officer: Curtis 8. Allen; Executive Vlce
`Preskfent and. Chief Flnanclal Officer: J. Crispin Ashworth: Senior Vice President-Corporate Operations: John R. Ware; senior Vice President-Corporate Business
`. Development: Raymond M. Zoeller; Vice President. tnfonnatlon Serllces and Chief lnfonnetion Officer: Edward J. Zecchini
`·1sBNs: 1-56363-152-0 an'-1-563~3-156-3
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`Celltrion, Inc. 1051
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`"
`~/P.HYSICIANS' DESK REFERENCE©
`..:.....~~~~~~~~~~~~~--.-~~~~-=-~~~~~~~~~-,...~~~~---,,---~~~~~~~.._,
`Astra-Cont.
`the bile or .recea lo seven days. hnpalrment ot liver fu~ \
`NOTE! . Do not UH the Injectidn if it ia darker than 1lightly
`yellow or dlscolored In any way.
`results in slower excretion, and wnaequently, inc~ ·
`retention ond accumulation in pluma and ~ ·
`021861R07
`Doxorublcln cloe9 not Cl'OS6 the bloocl brain barrie.r.
`INDICATIONS AND USAGE
`hi.jectabJ. doxorublcin hydrochloride haa been ustd ~
`Cully to prod ace rep-mi on in dissemiJlated MOplut:ic ~
`tions such u foC\lte lymph00188tic leukemia, 1CUte ~
`blutie leubmia, Wilma' twnor, neurobl.utoma, soft ti-.
`and bone aarcomu, lmaat carcinoma, ovarian car~
`transitional cell bladder carcinoma, thyroid can:inoma, ~
`phomoa or both Hodakin and non-Hodgkin typ.., bl'Oltcbo,
`genie carcinom in which the $11lall cell hiatologic type lathe
`m~ responsive compared to other cell types and ·8'Sllit
`·
`·.
`~oma.
`A number of other aolid tumors have abo ebo'l"t 90llle "(cid:173)
`sponsh•eness but in numbers too llmlted to jullify SpeQ&
`recommendation. Studies to dale have ihown maUcna.i
`melanoma, ldd.ney cardnoma, large bowel carcino!Da, "'(cid:173)
`twnors and metutases to the central nervOlll ay1tem not Ill
`be significantly responsive to doxoru.bicin therapy.
`:
`CONTRAINDICATIONS
`Doxorubicln therapy should not be ·11.arted in 11atienta •bo
`have marked ~losuppression· induced by previous ~
`ment with other antitumor sgenta or by radiotherapy. Coq.
`elusive data are not available on pre-existi.nf heart disease•
`a co-factor of increu.d Jilk of doxorubicin induced cerdile
`toxicity. Prelimlna?Y data suaast I.hat in such cases cardloe
`toDclty may occur at d068S lower than the ~
`cumulative limit. It bl therefore not recommended to 1tait
`.doxorubicin In audl c83es. Doxorublcin treatm111t la aioab.
`indical4d fn patlenta who received previous treatment will
`compl•ta cumulative do&e! or doxorub!cln and/or daunanibj.
`cin.
`.
`.
`
`~ OQlo ~ ~ H
`
`• HCI
`
`~ ~11•HCI
`M.W.•S7f ...
`NH,
`Doxorublcill binds to nucleic acid's, presumab\7 by apecirtc
`intercalation of the planar antbracycline nucleus with the
`DNA double helix. Tbe anthraqeline rint ia lipophilic but
`the saturated end of the ring system containe abundant hy·
`droxyl groupe adj-.it to the amino auiar, producinf a hy(cid:173)
`drophilic center. 'l'be molecule is amphoteric, containing
`acidic functions in the rill& phenolic rroups and a buic f\lnc(cid:173)
`tion in the sugar amino group. It binda to cell membranes as
`well as plasma proteins.
`.
`Doxoruhicin Hydrochloride Injection, USP la a sterile, Iso(cid:173)
`tonic, preservative-free aolution for Intravenous adminiatra;
`tion. It is available in 10mg(6 mL), 20mg (10 mL),60 mg(25
`mL)single dose viala and 2 mg/mLUOO mL)multi-dOM 'rial.i.
`Esch mL contains 2 1111 doxorubicin hydrochloride and the
`followin( inactive ingffilients: &Odium chloride 9 mg and
`water for Injection q.a. Hydrvcboloric acid is used to adjust
`pH to a target pH or 3.0.
`-
`Doxorubicin H,ydroehloride for Injection, USP, It 111pplied aa
`a et.rile, lyophillzed powder in vials containfue 10 mg, 20
`mg, or 60 mg of doxoiubicin hydrochloride, which, when
`reconstituted accordine to directions with a aultable diluent,
`produces a 1terUe, lsotonlcaolution, for !ntravenousadminis- ·
`tratioo, oontalnlllf 2 mg/mL of doxorubicin ~hloride.
`Each vial also' contains 60 mf, 100 me. or 250 m&o rapec(cid:173)
`tively, of lactolie monohydrate.
`CLINICAL PRARMACOLOGY
`Though not completehr elucidated, the medlanlam or a.ction
`of doxorublcin bl rela!ed to its ability to bind to DNA and
`inhibit nucleic acid ayntbesia. Cell culture ltudiee have dem·
`onstrai.d repid cell penatr.tion and perinucleolar chroma(cid:173)
`tin bincline, rapid inhibltion of mitotic actMt,y and nucleic
`acid 9)'Dthetls, mutaaenesis and chro-mal abenatlons.
`Animal studies have ahown activity in a 1pectrum or ezperi(cid:173)
`mental tumors. immunoeuppression, cardnogen.io proper·
`ties in rodents, induction of a •arlety of toxic effecta, includ(cid:173)
`ing delayed and pf'08JtSlive cardiac toxicity, myalosuppres(cid:173)
`aion in all species and atrophy to ~ in rala and dogs.
`Pbarmacoldzlet;c ltudlee show the intraveDOUS adailnistra·
`tion or normal or rad.iolabeled doxonibicin is follond by
`rapid plasma eleuance and sipificant tlaue bindiQC. Uri(cid:173)
`naiy excretioa. ae deterlllitred by fluorimetric metbode,.ac(cid:173)
`counts for approxlmately.f to6% of the administendd-ln
`lift days. Biliary exCretlon represents the 1118jor excretion
`route, 40 to 6090 of tho administered d011a being recovtred In
`
`WARNINGS
`Special attention must be given to the cardiac toxicity e.llu'b(cid:173)
`ited by cloxorublcin. Although uncominon, acute left Vlll!OO
`u1ar failure hu occurred, particularly In patientt who haft
`received total dosage of the ~ exceedin( the cwreoU,
`recoaunended limlt or 550 mg/m • This limit appean to be
`lower(~ mr/m1? In patients who recei.W ra.diotbtt1111to
`~ mecllat.lnal area or conmmitant lherapY witb other pO.
`tentially cardiotoxlc agenta such as cyclopbOlphamift. Tiie
`total dole of c!Oxorubic:in administered to the indiviclllll pt(cid:173)
`tient should aleo take loto eccount prrrioua or concomll&ot
`therapy with related compounds ruch u daunorublcln. Con(cid:173)
`gestive heart failure and/or cardiomyopathy may be encoun(cid:173)
`tered 1everel wee.ks alter discontiiiuatlon of do11orllhicin
`therapy.
`Cardiac fallu.re Is often not favorably affected by praen!IJ
`known medical or phJSical therapy ror canllac euppart.
`Early clinical di1g11osis of drug induced he.rt failure ap(cid:173)
`~to be essential for successful treatment with digilU,
`diuretics, 1ovr aalt diet and bed rest. Sevt{e cardiac toxidtJ
`ma)' occur preciJitoutl.r 'l'itbout antecedent ECG cbanga A
`baseline ECG and ECGs performed prior to each cloee or
`COUflHl a.ftar 300 rng/mZ cumwative dose bu been given II
`sugested. Tranaient 'ECG changes consisting ofT·wav1 o.t(cid:173)
`ten.ing, S.T depression and arrhythmiu lastlne up to two
`weeks after a doec or coune of doxorubicin are presently not
`considerecl lndicati.oM for ruspeneion of doxOt"Ublcin IM·
`apy. Doxorubicln cardiomyopathy has b.en reported to be
`assoc:iat.d with a persistent reduction Ill the voltage or the
`QRS -ve, a prolonption or the systolic time inteMI and I
`recluction ol the ejection fraction ae determined by echoclr'
`have ,_t been confirmed to comiatentl.y identi.(y those iD<i
`diggraph:f or 1'8.dlonuclide aniioeraJlhy. None ol these tesll
`vidual patients tMt are approaching thtir maxlinall,y toler(cid:173)
`atecl cumulative dole of doxorubicin. Ir tat retUlta inc1XF
`change in cardlac function B&SOCie.ted with cloxorubk:in, Ille
`beiiefit or continued therapy must be carefully eVflua~
`against the rillt of produciJli irrevers1'ble cardiac damage.
`Acute lif.threataning arrhythmias have been reported lb
`O«l1J' du:rinc or within. a few houn after doxorubicill h~
`chloride admlnisj;ralion.
`There iu high incidence of bone marrow deprsslon, primlJ'
`ily of~. requiring careful hematologic monltoriof
`W'lth the ncommended dosage schedule, leultopenla is 1$
`ally transient, reachingitenadiratlO to 14 cla11aftutrui(cid:173)
`ment with recovery usually occurrinf by the 21.t day. ~
`blocd cell counta ae low as 1000/mm are to be expected d1ll'
`ing treatment with oppropriate doses of doxorublcin. Bed
`blood cell and platelet levels should aleo be monitored .uice·
`they may tlao bo depnmed. Hematolqfic toxicity ma1. ~
`quire dose reduction or su.spenaion or del'IY o( doxoru~
`therapy. Paniatent severe myelosuppresaion may result 11
`auperinftetion or·hemorr~e.
`Daxorubicln may pot.entiate Iha toxicity of other anticaACllf
`lberaplet.. Exacerbation of cyclopbosphamlde induced ~
`orrbltgic eyltitie and enhanoement of the hepatol.oXicil>"~
`fl.mercaptcpurine have bees) repo1Ud. Radiation Jnd_.
`~ty to the myocardltu11, muC01ae, akin and liver ~
`been reported to be increased by lha administration '"
`doxorub!cln.
`
`"_j
`
`3/.92 (7)
`
`lJ,
`
`OOXORUBICIN HYDROCHLORIDE
`INJECTION, USP
`DOXORUBICIN HYDROCHLORJDE FOR
`INJECTION, USP
`[do:c.o.rabe •.IA.ftll J
`FOR INTRAVENOUS USE ONl Y
`
`WARN INGS
`1. Severe local tissue necrosi8 will occur lftbero ia extra·
`vasatlon during ad.miniskation (.tee DOSAGE AND
`ADMINISTRAT!ON).Doxorubicinmllltno~beg!ven
`by the intnmlllCUl.ar or subcutaneous route.
`2. Serlo111 irrevertible myocardial toxic!ty with delayed
`conceativa failure often UnrelJIOnslft to any cardiac
`supportive therapy ma,y be enco11nteNCI ae total dos(cid:173)
`age· approachee 550 ~m2• This toxicity ma,y occur
`at lower cumulative dosa In patients with prior mecl.i·
`aatinal Irradiation or on concurrent cyclophoepha·
`mlda therapy.
`3. Dosage ahoilld be reduced in patients with impaired
`hepatic function.
`·
`4. SeYet'e ~Olllppression may occur.
`5. Doxorubicin tbould be administered on\7 under the
`111penision or a ph.yl!cian whoia experienced in the
`use of cancer chemotherapeutic agent&
`
`D~CRIPTION
`Doxorubicin la & cyto(oltic anthracycline antibiotic iaolated
`from cultures of StrtplOmJea peuceUui var. caaiu& Dox(cid:173)
`orubicin conSists of a naphtbacenequlnonc nucleus Unlted
`through a gl,ycosld!c bond at ring atom 7toanamino111gar,
`dauriosamlne. The structural formula la a follow.:
`
`Dalgan, like other oii.xed aaonist-antagonist opioid analg~
`sics, bas low abuse ·potential in petient populations. How(cid:173)
`ewr, stronc mixed l(Onisw.nta(onlstclrup have reoortedly
`been associated with ebuse and dependence in hHlth-care
`providers and othera with rudy access to 111ch drup. Dalpn
`should be handled acoordfogly.
`Manufactured by:
`Wyeth Laboratories Inc.
`Philadelphia, PA 19101
`Mahufacturecl for:
`Aatra USA, Inc.
`Westboro, MA 01681
`0215'15ROO
`
`(8/94)
`
`50% DEXTROSE
`[do:'lnlR]
`Injection. USP
`Concentrated OtX1ro11
`For Intravenous
`Admlnlrtratlon
`
`NOTE: This solution 19 hyp41r10nlC>-Ste WARNINGS and
`PRECAUTIONS ,
`(For details of indica\lons, dosage and admi.niatration, pre(cid:173)
`circular In paekap.)
`cautions, and adverae reactions, -
`HOW SUPPLIED
`509' Dextmse Injection, USP la wpplied u foUOW1:
`50 m.L PrefJled Syringe with 19 Gllifis" needle, NOC 0186-
`~1
`The solution should bo 1tored at controlled room tempera·
`tUfl! 15'-30'0 (69'...aG'F).
`021857R06
`
`Rev. 10/94 (6)
`
`DOBUTAMINE HYDROCHLORIDE
`INJECTION
`
`DP.SCB.IPTION
`Dobutamine Hydrochloride Injection Is l,2-be112enediol, 4-{2-
`fi3-<4-hydro~henylH·metl\ylpropyll aininoJethyl)-. bydro(cid:173)
`chloride, (±)..It is a eynthetic catecholamine.
`
`Moleaalar Formula: CieffnNOa • HCI
`.
`Mole<alar Weight: 337.85
`'l'he cllnlcal formulation is 1upplied ~a sterile form for in·
`travenous use on\y. El.eh mL contains dobutamlne bydro(cid:173)
`chloride eciuivalent to 12.5 m& (41.6 )'mo[) dobutamino, 0.24
`mg sodium metabisullite (added during manufacture), and
`water for injection, q.a. Hydrochloric acid and/ or 1odium
`hydroxide may have been added during manufacture to ad-
`iust tbe pH.
`·
`Single dose vial. Discard unused portion.
`BOW SUPPIJED
`NDCOISS-1931-01, 20mLaiagle dose 'rial containing 2ro mg
`dobutamine (as the bydrocblor!de). box or L
`Store at controlled l'OOID tempel'8.ture 15'-SO'C (69'-86'Fl.
`Ceution: Federal law prohibits dispensine 'l'ithout pre(cid:173)
`scription.
`021648ROS
`
`lss. 8/94
`
`DOPAMINE HCI ln)eC1ion, USP
`[d6-Jlll-lmlln I
`.
`
`(For details of indicatiaos, dosage and administration, pre(cid:173)
`cautions, and advene iuctiQllS, see circular ln packaceJ
`HOW SUPPLIED
`Dopamine HCI 200 mg It supplied In the following form:
`Additive Syrinee 6 mL (40 mglmL) NDC 0186-06SS..Ol
`Dopamine HCl 400 mg la supplied in tba following fonna:
`Additive Syringe 6 mL (80 mg/mL) NDC 0188-0641-01
`10 mL (40 mg/mL) NOC 0186-0639-01
`Dopamine BCI 800 me Is eupplled in the following form:
`Additive Syrlnp 5 mL (160 mg/mL) NOC 0186-064~1
`Packaces are colof coded llCCO?ding to the total cbace con(cid:173)
`tent; 2.00 mg coded blua/'Wblte, 400 mg coded creenl
`white and 800 mg coded ,ellow/white.
`Store at controlled room temperature 115'-00'C (59'-WF).
`Protect frmn light.
`A void contact wi.th tlkalies (including &odium bicarbonate),
`oxidizing arente, or iron ealta.
`
`I " ...._
`
`
`
`2 of 12
`
`Celltrion, Inc. 1051
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`·r :,
`
`'
`
`,
`
`~:· c:illlthouldmonitorthepatleut'ab
`
`TIXU
`
`1
`
`Taslci;;::;;:;;.ty~to;;r:;;;ecoa;;;;;;:,m;;;:e:;o;;tded:i:idales:=;;:ot:t.&:i.:o:xo:ru~blcln:W::i:hydrochlorl::::;:::;:;::;de:;:-r:ra::;:tio;::os:::an::d;:di;;:.ure=:t;:ics.:-Th~e-:uae-:-:o-;rpe--:r!:-:phe:--ral:-'fNOdila--:-::-. -:-f.ort--:hu:---r-:NDC=-::--:O-l--86-1-53""'.Z-6_1_P:_::R:_:O~D:::U~C.'..T~IN:F:O~R~M=A.'._Tl~O:N~/_::54~1~
`
`ii enhanced by he~ impairment, therefore, prior to the
`been recommended.
`jDditidual dosinc. evah1atloii o1 hepatic functioo ;,, recom· DOSAGE AND ADMINISTRATION
`2 Jlli/mL.
`50 lllf-rial.
`25 mL.
`Box of L
`#adetl ~ c:ottqfttlonaJ cllnlcal llboretory t•ta. lllCb
`Store under refrigeratimi 2'C fo 8'C (36'F to 46'Fl. Protect
`., sGOT. SGPT, elb.line phosphatase encl bllkubin. (>'lee Care in the admlnist:atioo of dollorubidn h,Jdtochlorida will
`from light. Retain in car1on until time at UJe.
`•
`redute the chance of periftnous lnJUtn.lioo. It may al8o d&- Mui~ vial, contains no preservatives.
`))OSAGE AND ADMINISTRATIONJ
`•
`c::reaM the chance of local ~ons such es urticaria and
`NeerotWlll colitis manifested by typhlit» (cecal inf1amme.
`etythematoos streaking. On intn.veDOU lldminiatralioo of NDC 0186-1632-81
`tjotl),bloocb'atoolsandrevereandtometlmesfatalinfediona
`ba'-e been aaocla~ witli a combination or doxorubicin h7-
`doxorubicin, extravasa~o may OCCW' with or without &11
`. Bolt ~f L
`-100 mL,
`2 111(/mL,
`200 DI( vial,
`droclJ!oride gittn by IV push daily for S da)'I and~ accompanying stinging OT burning seuatlon and even It Store Wider -'-'-tlon. 2'C to 8'C (36'F to ,.,.,,. .,,._,_.
`·~....
`flYIR by continUOU$ infusion cla1J,)' for 1 or more cla.yw.
`bloodretunisMllonupiralioooftheinfmioollftdle.Ifany
`..., .. ,. ""'""'"
`from l!iht. RdailJ in carton until CODleuta are uled.
`()Jl inir9VCDOU8 admlnistn.tiOD Of doxorublcin, utravasa-
`sigD8Of1!)'11lptoms Of extravuatioo have OCCu.rnd, the injec•
`lion may DCQJr with or witbou~ an accompan,ying stinging or
`tloo or infusion should be immedia.tely termltsa~ and re-
`Ooltorubicin Hy~orlde for Injection, USP, ia aupplied in
`lblil• d<1a vials as a sterile red-orange lyophillied powder.
`bGtDine 1ensatiou aJ)d .ven if blood reluml MU 00 aapim·
`ltarted In another vein. If It ls knOWll or suspected tbat ruJ>.
`tiou of the infusion n~le ~ DOSAGE ANll ADMlNIS.
`The viab are peck~ in individual cartons.
`cutan"'1Sextravaaation bu occurred, local infiltration with
`an injectable corticosteroid and Ooodlng tM 1ita With nor-
`'!'RATION>. If any sigD8 or symptoma.of llttravasatlon have
`NDC Ol86-l5SS-2S
`10 1111
`occurrtcl, the injection or lnfutloo ehould be immediately
`. mal saline has been reported to leuen the local read!on.
`Product No, 1530-13
`-
`tenninated and restarted in another veln.
`Because of UM! progressive nature or extravuation TCGctiom,
`the area of lajection ahould be frequently examined and
`Dosorubicin ud rt Id tad compounds have also been ihown to
`plastic aurgery consultation obtained. If ull:$ratlon be-
`bafe m11tageolc and carcinogenic properties when teated in
`gins, early wide u:ci81oo of the involved lttA ahould be ·
`experiuiental mojfeJ1.
`.
`usage In p1t9nency-Sal'e wse of doxorubicin has not been
`considered'.
`.
`•
`establilhtd. Ooxorublcin la embeyotoxic and teratogenic in The mo&t commonly med dosage schedule Is 60 to 75 mg/mt
`as a single intravenous injection administered •t 21 d_, in·
`tall and enibryotoxic and abortifaeient in rabbits. Therefore,
`terv~The lowerdaseahouldbegiventopalientswithinad-
`the benents to the pregnant pat!ene ehould be carefully
`• weighed agal!ut the pottntlal toxicity to Crtus and embryo.
`equate marrow reserves due to old age, or prior therapy, or
`'!'he possible adverso elreda on femtlty in male.t and females
`neoplutic marrow infiltration. An alternative doeege ached·
`ule Is weekly does of 20 mg/m2 which has.been report~ to
`hi humaDI or esperimental animals have not been ade-
`qu1tely evaluated.
`produce a lower incidence of co1111estive heart failure. Thirty
`(30) mg/m2 on each of three ruccelllive da)'I repeated·eftry
`piu1£AtlTIONS
`.four '(t'eeks has also been !lied. Doxorub!dn dosep muat be
`,
`loitlal treatment with domrublcin ""lllires close observa·
`(
`reduced if the bilirubin le elevated u follows: serum bUiru·
`bin 1.2 to S.O mglc!L-1ive ~normal dose, >S m•/dL
`liouofthepatientandextcn1ivelaboratorymoaitoring. ltia
`f
`-tive 14 normal d-.
`·~
`reco1111t11!MHd, therefore, that patients be hoepilalized at
`I
`~- I~ during the flltt pha!e oC the treatment.
`Rec:anstiMion Direeliona: Doxorubicin l:bdrochloriae for
`'-'ectio 10
`""
`_,_,_ L-•• uL. __ _.,
`" Likeothercytoeoxicdn(p,doxorubicinmavinducehypmi-
`d""
`0
`i , ncemla~"'tortpid" •-mofnj:flastfc•at•-Tue-"-'·
`• m_J,..,mgau uvmf'"""'""""'"".........,...
`.....,
`I:''
`.,
`v
`-
`...
`tuted with 6 mL, 10 mL and 26 mL, -pectlvely, of Sodium
`uricecidlevelandbe Chloride Injection o~ to cm a rma1concentrationof2
`own
`. piepared to 1111 auch rupporti.ve and pharmacoiqpc mea· mglmL of doxorubicin b,Jdrocbloride. An app,.,,,riate YOI·
`as illigbt be nec:esury to control this problem.
`of · abould be
`·thclra
`'
`· th ·:;_r_,
`-
`) Doiorubicio impe:t.s a red.coloration to the urine for 1to2 "-
`e TIIU during
`wo arom
`air
`wi
`..._after edminlstratlon and-"--'- -L---'d be ad·-'-' to
`r-ecomtitutioo
`to avoid ezcessive prelSUre builckp.
`-1•
`.... -
`""""'
`Bacleriostatic diluent& are not .-mended.
`After adding the diluent, the vial eJiouJd be ahalttn and the
`expect this during active tbenpy.
`contents ·allowed to diSIOlve. The recollltituted IO!utioo ii
`Doxonibicin is not an anti-microbial apnt.
`liable for 24 houn at room temperature and 48 holl:s under
`ADVERSE RBAcrIONS
`.. Dooelimitl1liloldciti•oftherapy111Cmyc~ppressionand
`refrigeration 2'Cto8'C(S6"F to'6'F). Itthould beprot«ted
`Cro_m expo911n"to aunlight. Diacud uy uollled aolutloo from
`canllotoidci~ C- W ARNlNGS). Other rei.ctlon.s reported
`the 10 mg, 20 mg and ISO mg single dose vials.
`.. -.; ate
`: Cwneous-Revmible and comple16 alopecia occuni in No1C Parenteral drlllf products lhould be inspected vieu·
`·ally foT particulate matter and dlacoloration pri4r to admin·
`. - i cues.
`latrat!oo,-,whenever eolutloo and i:ontainer r:rmit.
`' Hnerplg)ntntation of nailbtdt and dermal~ primer-
`It is recoriuotnded that doxorubicm be alow y admlnbtered
`'· Uy in childmi, and ouycholyais have been reported in a rew
`'.' case& ~II of akin roaction due to prior radiotherapy has
`into the tubing of a Creel)' ruDlling intravenOlll inflla!on of
`· occunecl with doxorubicin adminiatntiou.
`Sodium Chloride Injection or Dexltcle Injection, 5*'. The
`~ O.rtro1111 .. tin1l-Acute oaUIU and vomilin,r occurs ·fre.
`tubing should be attached to a Butterfly® needle Inserted
`preferably into a large vein. It possible, avoid \reins over
`' ~nt!y and may be aevere. Thia may be alleviated by anti&-
`.. 'metlc therapy. Mucositis (stomat!tla and esophagi&) may
`joints or in extremitiea with compromised venoue or lym·
`occur 6 to 10 days al\er aclmln.latratlon. The etrect may be
`phatic draioage. The rate of lldminl.ttration ia dependent on
`; . eevere lead ins to ull:$ratlon and represents a site of origin
`the size of the win end the d06llge. However, the dose ahould
`5 fo! wver~ Infections. Th~ .doeage regimen coDliating or ad· . be administered In not less than 3 to 5 minutes. Local ery·
`IDinlshation of doxorub1cin on three consecutive days re-
`tbematons streaking along the vein"" well es facial Oushlng
`"· !U}ll in the g?tater lncide11<:e and severity of mucosltis. tn· m_, be indiCative of too rapid an admlnlstratlon. A burning
`'!lfrat:lon and necroela oftho colon, especially the cecum, may
`or stinging sensation may·be Indicative of periveno111 inft!·
`tration and the infusion should be immediately terminated
`·. occur leading to bleedllll Or severe lnfecijoDI which can be
`and restarted in another vein. Periveoous infiltration may
`' fatal. Thia reaction bas been reported In patteota with. acute
`. ~11-lymphocytic leukemia treated with a 8-dey course of
`occur painlessly. Oo1tor11bicin ihould not be milted with hep-
`': :!i'~rubicin combined with cytarabine. Anoruia and diar·
`arln or fiuorouracil aince it bas been reported that these
`· mea have been occuiooally reported.
`·
`drup are incompatible to lhe extent that a precipitate may
`form. Until apecific comp'atibillty data are available, It is not
`\ )'aoculer- Phle*lerlllia h.. been reported especially
`: '!hen small ttins are used or a single vein is used ror
`recommended that domnibicin be mixed with other~·
`-~~ ad~tion. hcial 0111hing may occur If the Doltorubicin bas been used coocumotly with oilier ep-
`J~Jectfoo is pvtn too rapidly.
`prom! chemotherapeutic agent& Evidence is avaJ!able that
`, ~'75--• callulitis, vesication and tissue necrosis will
`in some types ot neoplulic disease combination chemothtl'-
`~ dOl!Ofllbidn Is extnvasated darillg administration.
`apy ia eaperior to single agent& The beneflta and Nb of
`· ~~~~~i!m~~lDL~A~i118~ ~':::.1!~ ~~= tos:O'=usoc1atec1withc1ox •
`·
`·
`• . ~""'·"'"TION.)
`orubicio have b:een repOrted. Caution in the handling and
`:!!'~•lti.vity-Fever, chills and wticarla have been ~ preparation at the powder and aolutlon mu.st be um:iled
`and th& use of gloves is recommended. If doxorubicin powder
`.::~-OCC83ionally. Anapb,ylu!I may occur. A case of appar-
`crosa sensitivity to llnOODl)'Cin bas been reported.
`OT solution contacts the akin or mucosae. immediately w .. h
`,
`.~r-ConJunctiviU. and lacr!matlon occur rarely.
`thoroughly with soap and water.
`Procedures Cor proper haJldling and disposal of anti-cancer
`}lvtRI>osA:GB
`·
`·
`1~ o . e.
`. . . .__ ot doxorublci"o e-L . __ •L-tolUC' elli~-'- of drugs should be considered. Several suidolines on thia lub.
`:.!'11CiOSilis,·~ unan-"""
`"'""
`ject have been publWiecl.H There is no general agreement
`:l!Cule
`eukopenia and thrombopenla. Treatment of
`tbatall of the proc.duree teeommonded in the guidelines are
`· ·
`overc1osag9 ·consleb of treatment oC the eeverely
`necessary or approprla.te.
`~flatelet PPresRd patient with boepltallzation, antibiotial, HOW SUPPIJED
`and sranulocyta tra~ and symptomatic
`• · ~tor mucosltla. The 200 mi vial is paekued as a mal· Doxorubicin Hydrochloride Inject!oo, USP, ls sllpplled aa a
`. · e:n vial and caution ehould be eurclseCl to prevent
`sterile, red-orange solution. Single dose vial, contains no
`t overdoe.,e.
`. pre&ervatiws. Discard 11n118ed portion.
`.
`.
`' · 'llJ.!f. overdosap with cumulative doet1 Hceedinr 660 . NDO 018$-1632-Sl
`· IDCreues the risk or eardiomyopat.hy and resultant
`10 mg vial, ·
`ve heart £allure. Treatment conaiate of vigorous NDC 0186-1632-41
`20 mg vial._
`einentof congeetlve heartCaiJurewithdlgitalia prepa-
`
`NDC 0186-1534-28
`Product No. 1531-01
`S.tore unreconstituted vials at controlled room temperature
`16'0 to 3a'C (59'F to 86"F). After reconstitution the .eolution .ill
`ateble Cor 7 days at room temperature and 1lS de,. under
`refrigeration 2'C to 8'C (36'F to 46"F).
`Proi.ct from light. Retain in carton until contents are used.
`Discard usnused portion.
`.
`·
`Ceutlon: Federal law pr-ohibits dispellling without pre(cid:173)
`tcription.
`REFERENCES
`1. RudolphR,etal: Skin UlcersDuetoAdriamycin,Caocer
`1976:38:1081-100. ..
`2. Recommendations for the Safe Handlinc. oC Parentei-al
`A.utl.oeoplatic Drup. NIH Publication No. sS-2621. For
`aa!e by the Superintendent o( Documents, US Gonm(cid:173)
`ment Printing Ollice, Wub.lngtoa D.C. 20402.
`3. AM.A Council Report. Guidaliu• for Handling Parenteral
`Antineoplutic& JAMA. Match 15, 1985.
`·
`4. National St111\y Colllljlisajan on Cytotoxic BxPosure(cid:173)
`Recommendatiooa !or Handling Cytotosic Agent:o. Avail·
`• able from Louis P. · Jelfrey, Sc.D.; Chai:nDan, National
`$tUlfy Commillloo OD Cyto~c l!xpoeure. Maiaacbuaetla
`College or Pharmacy and Allied Health Sciences, 179
`Loopood Attnue, Boston, Mamachusetta, O'Jl16.
`5. Clinical Oncological SocMty of Autralla: Guidelines and
`recommenclailone for safe handling of antlneoplastic
`iient&. Med J Australia 1983: 1:426-428.
`6. Jones RB, et al. Safe handling of chemotherapeutic
`egenta: A RePQrt ffOlll the Mount Sinai Medical Center.
`Ca·A Caneer Journal for 'Clinicians Sept./Oct., 1983:
`258-263. .
`.
`.
`7. American Society ofH09pital Pharmacista Technical A&(cid:173)
`aistance Bulletin OD Handling Cytotoxic and Hazardous
`Drup. Am J Hosp PbAnn 1990: 47:1033-1049.
`MANUFACTURED FOR:
`Aatra USA, Inc.
`Westborough, MA, 01681
`DATE:
`Octobei- 1994
`MANUFACTUREO BY:
`PHARMACHEMIE 8.V.
`HHl1em
`The Ne1htl1enda
`
`·
`
`Box·of II
`
`20 mg
`
`NDC 0186-1636-28
`Product No. 1575-12
`
`80 mg
`
`Box ors
`Box ofl
`
`02F94R01
`
`93.144.101.C
`
`~
`DllOPERIDOL INJECTION, USP
`FOR INTRAVENOUS OR INTRAMUSCULAR USE ONLY.
`
`(For details ol Indications, cllJ&a&e and administntioo, ~
`cautiooa, and advene reactions, -
`circuW in package.)
`BOW SUPPLIED
`Droperidol iAjectiou is a'!811able as:
`Ampulu, 2.6 mg/ml
`·
`2 mL, (6 mg/2 mL>.
`bolt of 10 NDC 0186-1220-03
`box or 10 NDC 0186-1221-03
`6 mL, (12.5 111(/6 mL),
`Single Dose vrar.. 2.6 mg/ml
`2 mL, (6 mg/2 mLJ,
`. box or 10 NOC 0186-1226-lS
`box of 10 NDC 0186-1227·13
`15 mL, 02.6 ID(/5 mL),
`Multlplt Dou Vlel1, 2.6 mg/ml
`10 mL,
`box of 1 NDC 018&.1224-12
`PROTECI' FROM LIGHT. STORE AT 00?\'TROLLED
`ROOM TEMPERATURE 15'-30'C (59'-86"F).
`021879ROS
`'
`
`REV. 2/96
`
`•
`
`Contin~d. on next pafl• .
`Consult 1!196 supplements and l'utwe oclillona for rovtslons
`
`2 mg/mL,
`
`2 n:-g/mL,
`
`llmL.
`10 mL.
`
`Box of l.
`
`Box ofl.
`
`
`
`3 of 12
`
`Celltrion, Inc. 1051
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`I :
`
`712/PHYSICIANS' DESK REFERENCE®
`
`Bristol-Myers Squibb Oncology-Cont.
`
`tient.a ~iving a relatively high cumulative dose of PLATI·
`NOL and with a relatively advanced symptomatic stqe or
`pcriphenl neuropeth)'.
`Oculer Toxlcity-()pliCl neuritis, papilledema, and cmibral
`blindness have been reported Infrequently in patient.a receiv·
`Ing standard recommended doses oC PLATJNOL. Improve(cid:173)
`ment and/or total rtCOVery usually oa:un aller dlscontillu·
`ing PLATINOL. $W-oid5 with or without mannitol have
`been \lied; bow9ver, efficacy hu not been established.
`Blurred vision and altered color perceplion have been r•
`ported after the use ot regimens with higher doaes of PLATI·
`NOLorgreaterdosefrequendealhan tboserecommtnded In
`the package inserl. Tht a1tend c»lor perception manifests.,
`a J.ou oC oolor discrimination. particularly in the blue-yellow
`axis. The only finding on funduscopic exam is fn-egular
`retinal pigmentation of the macu1ar area.
`Anephylactlc-lkt Raaetion-Anapbylact:ic·like re.actiont
`have been occuionall,y reported in patienta pnviously u·
`posed to PLATINOL The nactiont consist of facial edema,
`wheezing, tachycardia. and h,ypotension within a few min·
`ute3 of drug adminletration. React.Ions may be oontrolled by
`intravenous epinephrine with corticosteroicll, and/or an·
`tiblstalllittes as indicated. Patitnta recei"rinl PLATINOL
`should be obsened carefully for possible anaphyladio-llltt
`reaction• and supportive equipment and medlcation should
`be available to treat 1uch a complication.
`Hepatotoxlclty-Transient elevationa of liver enzymes, espe(cid:173)
`cially SGOT, as well as bilirubin, have been reported to be
`:issoclated with PLATINOL administration at the recom(cid:173)
`mended doses.
`01h1t Events-Other t.oxicitiet :.ported to ·occur infre(cid:173)
`quenU1 are carcllac abnonnalitlet, hiccup&, elevated aerum
`amylata, and rash. Alopecia has also been reported.
`Local soft liisue toxicity has rarely been reported following
`extravasaUon or PLATINOL. Severity of tho local tiaue
`toxicity appears to be related to the concentration of the
`PLATINOL solution. Inl\Jsion of solutiona with a PLATI·
`NOL concentration greater than 0.5 mg/mL may resnlt in
`tissue c:ellulitls, fibrolit, and necrosis.
`OVERDOSAGE
`Cautlon ahould be ax1tcised to prevent inadwrtmt o-do.
`age with PlATINOL. Acute overdoNge with this drqg may
`result in kidney (allure, li•er failure, deafn-, ocular toxic(cid:173)
`ity (including detachment of the retinal, aigniJlc:ant ID)'elo(cid:173)
`euppression, intractabla nausea and vomiting and/or neuri(cid:173)
`tis. In addition, death can occur following overclosage.
`No proven antidotes have been established for PLATINOL
`overc!-ie. Hemodialysis, min when Initiated four hourt
`after the overdosage, appears to h.ave little effect on remov·
`ing platlnum from the body because of PLA TINOL's rapid
`and biah degree of protein binding. Manacement ot overdos-
`age should include 1tt1eral supportive meuures to &UStain
`the patient thrCJ118h any period of toxicity that D1aJ occur.
`DOSAGE AND ADMINISTRATION
`Note: Nffdles or lntn1vanou1 tits containing aluminum
`par1& thtt m1