PDR
`
`EDITION
`
`2000
`
`PHYSICIANS’
`S DESK
`REFERENCE”
`
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`3°"‘°" ‘°°°|'"' M3188": Flank KGTKOWSKY
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`. C°DynghtO 2000 and published by Medical Economics Company. inc. at Montvaie. NJ 07645-1742. All rigms reserved. None at the content of this publication may
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`
`Lupin Exh. 1018
`
`

`
`Vlbl-E-Dose is ii registered trademark of Hoflmauu-La
`Roche Inc.
`'lbblets nisnufscturud by:
`Boehringer Mennlieiin, Gmbl-l. Mannheim, Germany
`Ampuls manufactured by.
`Abbott Laboratories. North Chicago, IL 60084
`Revised: April 1998
`shown. in Product Idlliflficatlon Guide, page 884
`
`EC-NAPBOSYNO
`(naproxsnl
`Delayed-Release Tablets
`
`NAPROSYNO
`(nspreiionl
`Tlbhb
`
`ANAPIIOXOIANAHIOXO D8
`ion’ d-proxl
`ineproxsn sodium)
`Tablets
`
`ROCHE LABORATORIESIZS31
`PRODUCT INFORMATION
`
`elisnmstiim linlf-life of naproxen is unchanged across prod-
`Dose
`Shape
`Bottle
`Tb]-E-Dose
`5 mg
`oval
`NDC 0004-0262-01
`NDC 0004-0262-49
`ucts ranging from 12 to 17 hours. Steady-state levels of
`10 mg
`oval
`NDC 0004-0263-01
`NDC 0004-026340
`nnproxen are reached in 4 to 5 days, and the degree of
`20 ms
`oval
`NDC 0004-0364-01
`NDO 0004-0264-49
`napioseu accumulation is consistent with this half‘-life. 'l1iis
`
`NDC 0004-U266-01capsule-shaped100 mg NDC 0004-0265-49
`
`
`suggests that the diflersnces in pattern if release play only
`a negligible role in the attainment of steady-stats plasma
`mg, 10 mg, 20 mg, or 100 mg, respectively). On the opposite
`Angioedsina has been reported in a patient exposed to
`levels.
`se.
`Absorption:
`rugs.
`msaghe tablet is debosssd with 6, 10, 20, or 100 to indicate
`li)EMADEX who was later found to be allergic to sulfa
`Immediate Release: After administration of NAPROSYN
`Of the adverse reactions during placebo-controlled trials
`DEMADEX for intravenous injection is supplied in clear
`tablets. peak plasma levels are nttumsd in 2 to 4 hours. Af-
`listed without taking into account assessment of related-
`iiinpuls containing 2 ml. (20 mg, NDC 0004-0267-06) or 5
`ter oral administration of ANAPBOX. peali plasma levels
`ness to drug therapy, arthritis and various other nonspecific
`are attained in 1 to 2 hours. The diflbrenca in rates between
`mL (50 mg, NDC 0004-0268-O6) of a 10 mg/ml. sterile solu-
`musculoelrelstal problems were more frequently reported in
`tion.
`association with DEMADEX than unth placebo. even
`the two products is due to the increased aqueous solubility
`Storage: Store all dosage forms at 15‘ to 30'C (59' to 86'1").
`though gout was somewhat more frequently associated with
`of the sodium salt of nspioxen used in ANAPROX Peel:
`Do not freeze.
`placebo. Thus reactions did not increase in frequency or as-
`plasma levels ofnaproxsn given as NAPROSYN Suspension
`are attained in 1 to 4 hours.
`verity with the dose ofDEMADEX. One patient in the group
`treated with DEMADEX withdrew due to myalgis. and one
`Delayed Release: EGNAPROSYN is designed with a pH-
`in the placebo group withdrew due to gout.
`sensitive coating to provide a barrier to disintegration in the
`Hypokaleniia.
`See WARNINGS.
`acidic environment of the stomach and to lose integrity in
`OVERDOSAGB
`the more neutral environment of the small intestine. ‘Ilia
`There is no human experience with overdoses of
`anteric polymer coating selected for EC-NAPROSYN.dis-
`DEMADEX, but the signs and symptoms of ovardosage can
`solves above pH 6. When EGNAPROSYN was given to
`be anticipated to be those of excessive plinrrnacologic effect:
`fasted suinects. pesli plasma levels were attained about 4 to
`dehydration. hypovolemia, liypotension, hyporuitrsmia. hy-
`6 hours following the first dose (range: 2 to 12 hours). An in
`pokalsniia, hypochloremic alkalosis. and hsmoconcentra-
`vivo study in man using rsdiolaheled EC-NAPROSYN tab-
`lion. Treatment of ovsrdossge should consist of fluid and
`lets demonstrated that EC-NAPROSYN dissolves primarily
`eledrolyte replacement
`in the small intestine rather than the stomach, so the ab-
`Laboratory determinations ofssrum levels oftorseinide and
`sorption ofthe drug is delayed until the stomach is emptied.
`its metabolites are not widely available.
`When EC-NAPROSYN and NAPROSYN were given to
`No data an available to suggest physiological maneuvers
`fasted subyscts (n-24) in a crossover study following 1 week
`(cg, maneuvers to change the pH of the urine) that might
`accelerate elimination of torseiriido and its metabolites.
`of dosing, diflbrvenoos in time to peak plasma levels (Tm)
`were observed, but there were no differences in total absorp-
`Tbrsemlde is not dislyzable, so hsiuodiaiysis will not accel-
`erate elimination.
`tion as measured by C“, andAUC:
`[See table at top of next page)
`DOSAGE AND ADMINISTRATION
`Aniacid Effects: When EGNAPROSYN was given as s sin-
`Gsneml- DEMADI-IX tablets may be given at any time in
`gle dose with antacid (54 mEq bulfenng capacity). the peak
`relation to a meal. as convenient Special dosage adjustment
`plasma levels of naproxon were unchanged, but the time to
`in the elderly is not necessary.
`Because of the high bioavailability of DEMADBX. oral and
`peak was reduced (mean T,“ fasted 5.6 hours, mean T”,
`with antacid 6 hours), although not significantly.
`intravenous doses are therapeutically equivalent. so pa-
`tients may be switched to and from the intravenous form
`Food Effects: When BC-NAPROSYN was p'ven as a single
`with no change in dose. DEMADEX intravenoiu iroectiou
`dose with food, peak plasma levels in most subjects were
`should be administered either slowly as a bolus over a pe-
`achieved in about 12 hours (range: 4 to 24 hours). Residence
`riod of 2 minutes or administered as a continuous infusion.
`tiure in the small intestine until disintegration was inde-
`If DEMADEX is administered through an IV hue. it is rec-
`pendent of fixed iiitalie. The presence of food prolonged the
`ommended that, as with other IV injections, the IV line be
`time the tablets remained in the stomach, time to first da-
`flushed with Normal Saline (Sodium Chloride lirlectiou,
`tectable serum naproxsn levels. and time to maximal
`USP) before and alter administration. DEMADEX irijectim
`naproxen lovels ('l‘,.,,,). but did not sifect peel: naproicen lev-
`is formulated above pH 8.3. l'-‘liishing the line is recom-
`els (C,..,).
`mended to avoid the potential for incoinpahhilities caused
`Distribution:
`by diflerences in pH which could be indicated by color
`Naprrixen has a volume of distribution of0.16 Ukg. At ther-
`II
`apeutic lsvels naproxen is greater than 99% albumin-
`fhthnfo, business or the for-matioo of a precipitate in the so-
`bound. At doses of uaproun greater than 600 mglday there
`IfDEMADEX is administered as a continuous infusion, sta-
`is less than proportional increase in plasma levels due to an
`bility has been demonstrated through 24 hours at rooui
`increase in clearance caused by samration of plasma pro-
`temperature in plastic containers for the following fluids
`and concentrations:
`tein binding at higher doses (avenge trough C. 36.5. 49.2
`and 56.4 inyl. with 600, 1000 and 1500 mg daily doses of
`200 mg DEMADEX (10 m#iiiL) added to:
`250 nil. Dextrose 6% in water
`naproiisn). However,
`the concentration of unbound
`260 mL 0.9% 8odiuni Chloride
`naprosen continues to increase proportionally to dose
`Metabolism:
`500 mL 0.45% Sodium Chloride
`Naproxen is extensively metabolized to B-0-desmethyl
`so mg DEMADEX (10 mg/mL) added to:
`500 mL Dextrose 5% in water
`naproxen, and both parent and metabolites do not induce
`500 mL 0.9% Sodium Chloride
`rnetabolisiiig enzymes.
`E!iminati'ori'
`500 mL 0 45% Sodium Chloride
`The clearance of naproxen is 0.13 murninlhg. Approxi-
`Before administration, the solution oi'DEMADEX should be
`mately 95% ofthe napsoiien from any dose is excreted m the
`visually inspected for discoloration and particulate matter
`urine, primarily as napiuxen (less than 1%), 6-0-desmethyl
`If either is found, the ampul should not be used.
`naproxsn (less than 1%) or their conjugates (66% to 92%)
`Congestive Heart Failure: The usual initial dose is 10 mg
`The plasma half-life of the naproxen anion in humans
`or 20 mg ofonce-daily oral or intravenous DBMADEX. Ifthe
`ranges from 12 to 17 hours. ‘Hie corresponding half-lives of
`diuretic response is inadequate, the dose should be titrated
`both iiaproxeifs metabolites and coiuugatss are shorter
`upward by approximately doubling until the desired di-
`than 12 hours. and their rates ofesrrrstlon have been found
`uretic response is obtained. Single doses higher than 200
`to coincide closely iritli the rate of naproxen disappearance
`mg have not been adequately studied.
`Chronic Renal Failure The usual
`initial dose of
`from the plasma. In patients with renal failure metabolites
`may accumulate.
`DBMADEX is 20 mg of once-daily oral or intravenous
`Special Populations:
`DEMADEX. Ifthe diuretic response is inadequate, the dose
`in pediatric patients aged 5 to 16 years
`Pediatric Puliarifs:
`should be titrated upward by spproinmately doubling until
`with arthritis, plasma naproiren levels following a 6 rndkg
`the desired diuretic response is obtained. Single doses
`single dose ofnaproiian suspension (see DOSAGE AND AD-
`higher than 200 mg have not been adequately studied
`MINISTRATION) weiu found to be siinilarto those found in
`Hepatic Cirrhosis:
`‘Ilia usual initial dose is 5 mg or 10 mg
`normal adults following a 500 mg dose. The terminal half-
`of once-daily oral or intravenous DEIIIADEX, administered
`life appears to be similar in pediatric and adult patients.
`together with an sldostsrona antagonist or s potassium-
`Pliannaookinetic studies ofnaproxen were not performed in
`sparing diuretic. If the diuretic response is inadequate. the
`pediatric patients younger than 5 years of age. Pharmaco-
`dose should be titrated upward by approximately doubling
`kinstic parameters appear to be similar following adminis-
`until the desired diuretic response is obtained Single doses
`tration of nsproiosn suspension or tablets in pediatric pa-
`hifiier than 40 mg have not been adequately studied.
`tients. EC-NAPROSYN has not been studied in aubascts un-
`Chronic use of any diuretic in hepatic disease has not been
`der the age of 18.
`studied in adequate and well-controlled trials.
`Renal Insufllclcncy. Naproseii pharmscoliiriotics has not
`Hyp¢:taisi‘on- The usual initial dose is 6 mg once daily. if
`been determined in subgecui with renal insuflciency. Given
`the 5 mg dose does not provide adequate reduction in blood
`pressure within 4 to 6 weeks. the dose may be increased to
`that naproiosn. its metabolites and conjugates are primarily
`excreted by the kidney, the potential exists for naproxen nie-
`10 mgonm daily ifthe response to 10 mg is rnsuflicient, an
`tabolites to accumulate in the presence of renal insuli-
`additional antihypertenaivs agent should be ndded to the
`ciency.
`treatment regimen
`CLINICAL STUDIES
`HOW SUPPLIED
`General lnlorrnatlon: Nnprosen has been studied in pa-
`DEMADEX for oral administration is available as white,
`tients with rheumatoid arthritis. osteoarthritis. Juvsrnla ss-
`scored tablets containing 6 mg. 10 mg. 20 mg. or 100 mg of
`thritis. ankylosing spondylitis, tendonitis and bursitis. and
`torssmlde. The tablets are supplied in bottles and 'l‘el—E-
`acute gout Improvement in patients treated for rheumatoid
`DoseO‘ packages of 100 as follows:
`arthritis was demonstrated by ii reduction in joint swelling,
`lSee table shovel
`Each tablet
`is debossed on the scored side with the
`Boehringsr lifsnnlieim logo and 102. 103, 104. or 105 (for 5
`
`NAPROSYNO
`[iiaproxenl
`Suspension
`The following text is complete prescribing information
`based on oflioial labeling in ofiect June 1999.
`DESCRIPTION
`Naproxen is a member of the arylaeetic acid group of non-
`steroidal anti-inflammatory drug
`The chemical names for napioiisn and napronsn sodium are
`(S)-6~msthoxy-o-methyl-2-naphtlialenesiufc acid and (Sl-6-
`msthoxy~o-methyl-2-naphtlielensaostic acid. sodium salt,
`respectively.
`Naproxen is an odorless, white to oil’-wliits crystalhns sub-
`stance. It is lipid-soluble, practically insoluble in water at
`low pH and freely soluble in whim at high pH The oitanoll
`wstor partition eoeflicient of napi-oiisn at pH 7.4 is 1 6 to
`1 B. Naproxen sodium is a while to cnianiy white, crystal-
`line solid. freely soluble in water at neutral pil.
`NAPROSYN (naprouren) Tablets contain 260 mg. 375 mg or
`500 mg of naproxsn and cioscarmellose sodium, iron oxides,
`povidoiie and magnesium stearate.
`EC-NAPROSYN (iiapioxen) Delayed-Release 'l\iblets are
`enteric-coated tablets containing 376 mg or 600 mg of
`naproxsn and oroscarmsllose sodium, povidoue and magne-
`sium stearaie. The eiiteric coating dispersion contains
`snetliacryllo acid oopolyruer, talc, triethyl citrate, sodium hy-
`droxide and purlliod water. The dispersion may also contain
`simsthiooiie emulsion. The dissolution of this enieric-coated
`uaproxen tablet is pH dependent with rapid dissolution
`above pH 6. There is no dissolution below pH 4.
`Each ANAPROX 2'15 mg and ANAPROX D8 550 mg tablet
`contains naproasn sodium, the active ingredient, with mag-
`nesium stearate, microcrystalline cellulose. povidone and
`tale. The coating suspension for the ANAPROX 275 mg tab-
`let may contain hydroxypropyl methylcslluloss 2910,
`Opaaprsy K-i-4210A. Polyetliylene glycol 8000 or Opadry
`VS-1-4215. ‘His coating suspension iir the ANAPROX E
`560 mg tablet may contain hydroxypropyl metliylcallulose
`2910, Opaspray K-1-4227, polyethylene glycol 8000 or
`Opadry YS-1-4216.
`NAPROSYN (naproxsn) Suspension for oral adniini'atratim
`contains 125 md5 ml. of naproxen in a vehicle containing
`sucrose, magnesium aluminum silicate, sorbitol solution
`and sodium chloride (30 mfli mL, 1.5 mfiql, mstliyipara-
`beu, fumaric acid. l"D&C Yellow No. 6, imitation pineapple
`flavor, imitation orange flavor and purified water. The pH i‘
`the suspension ranges from 2.2 to 3.7.
`CLINICAL PHARMACOIDGY
`Naproxsn is a nonsteroidal anti-inilauiuistory drug
`(NSAID) with analgesic and antipyretie pmpertiea The so-
`dium se.lt ofniiproiien has been developed as s more rapidly
`absorbed formulation of napioimn for use as an analgesic
`The naproxsn anion inhibits prostaglsndiu synthesis but
`beyond tlus in mode of action is unlinovni.
`Phsrmacoklnetles: Napruuien itself is rapidly and com-
`pletely absorbed from the gastrointestinal tract with an in
`vivo bioavailability of 95%. The difibreut dongs forms at‘
`NAPRDSYN are biooquiviilent in terms ofextent of absorp-
`tion (AUC) and peak concentration (Cw); however, the
`product: do differ in their pattern of absorption. These dif-
`ferences between naproxen products are related to both the
`chemical form of naproxen used and its ilorniulation. Bven
`wifli the obsrvcd diifereiices in pattern of absorption, the
`
`Bi
`
`1}
`
`B
`
`Bi
`
`Continued on naxr page
`
`

`
`2632/ROCHE LABORATORIES
`
`EC-Naprosyn/Anaprox—cont.
`
`PHYSICIANS’ DESK REFERENCE®
`
`EC-NAPROSYN’
`500 mg bid
`
`
`
`
`97.4 (13%)
`94,9 (18%)
`{W/mm
`C
`ii roduction in duration of morning stiffness. in reduction in
`-1-2:: (hours)
`4 (39%)
`L9 (61%)
`disease activity as assessed byboth the investigator and pa-
`AUco_mr(u8_h,,mL)
`345 (20%)
`757 (15%)
`mint, and by increased mobility as demonstrated by a re-
`duction in walking time. Generally, response to naproxen
`
`’ Mean value (ooeflicient of variation)
`has not been found to be dependent on age, sex. severity or
`duration of rheumatoid arthritis
`gross bleeding or perforation appear to occur in approxi<
`Annlguln/Dyamcnorrhn/Bursitis and Tondonitlu: Be-
`patients with osteoarthritis, the therapeutic action of
`mately 1% of patients treated for 3 to 6 months and in about
`cause the sodium salt of naproxen is more rapidly absorbed,
`2'70 to 4% of patients treated for 1 year.
`ANAPROX/ANAPROX DS is recommended for the manage-
`noproxeii has been shown by a reduction in joint pain or
`ment. of acute painful condition: when pmrnpt onset of pain
`tendemess. an increase in range of motion in knee joints.
`Physicians should inform patients about the signs and/or
`
`
`by a reduction in walk-
`symptoms of serious GI toxicity and what steps to take if
`increased mobility as demonstrated
`reli
`_’__
`
`
`mended starting dose is 550 m
`
`.
`‘
`_tn.ni-.r.fnrin_iictiv i
`.~i.:ir tam-=_.*m:!.i2\<\::tnwiiIe.i\!.,in tam '
`
`
`
`
`
`
`
`
`
`‘flno-rsvi-i-an-z=—1—u-..r~.
`
`uckhassnhsidell.ANAPll.0Xinnynhoheusedal.ashrt~
`
`InIttliefreqIe:iqImInveI'|ty¢Ithenililer|n.1tIointesh—
`ingdosed'B25ng|'olloI:edhyZ'l5ingeveI-yllioiinu
`
`
`nnIndveIneI[u:ln(nnnsua,¢lnpepsh.|ienrtbnm)andnu=-
`needoilEC«NAPIl.()SYNianiitm:mnmeIidedh¢cnnenflln
`voiIssyaliunarlverseelisn(tninitun,diuiiies,liglitheul—
`delayinahoiinitim(sseC[.lNlIALPHAll|lAO0U)GYl.
`e¢Inen)Iereleuinnnp:nnen-trealedpationuthaniii
` hwfidAmhfi$mdfl-
`lluaatrntedwilhuphinorincblnelhncin.
`tlu:'l'hcra:innn:mIeIldoIeofn:p:unni:NAPROSYNor
`lnpalienhwiflinnkylonngspondylitiynninnunhauheai
`NAPll0SYNSuapenaion260mg.3'l5rngor600ingtahui
`sliournIaodecmaoani¢|Ilpnn,niomIngsufl‘nenInIitlpninnl.
`twu:edn|ly(moI'nilgIlidevnilng)orB(‘rNAPROSYN3'l5
`xnklndouhle-hlilidshulieatludlugwnnolwwnhnbou
`ncor.'s00mgtnlw|hviee¢laily.NapmnnstidinninqnIun
`hensed(leeDOSAGIANDADllINISTRATl0N)-
`efluaiveasupinmhuwflhfewuoileofieds.
`Dulinglimg-leimndniinialnliiintliednleofnaprnmnniny
`lnp|timIswitIiuutogout,nl'nvonhIoruponuto
`napuiimiwnsllwwnhysigiiificnnldeuingofinflnnmauny
`healliustedupordowndzpendingontlieclinicnlrenpmse
`diangu(eg.decreuoinawellingheat)within24to48
`ol'flinpnIient.A|uIvertlnilydoneinnyliifl¢iirloIi(—f£rl|
`ndInininl.rn'uin.lnpatient:Ivhotol2nielivwu'dnaeaweI,
`¢hedonomayho|na'easodl.ol500Ingperdnyv1hnnn
`higlierhvelofmfianlanmntoqhulgesicaimvityiare
`qImed.WheriuunngpnIienhwithnnprounn1500mydny
`(uNAl’M)SYNor16l50in¢dANAPll.0X).Ihephysidan
`alininlxlolbalvnsufiziitmncnaedelinitnlhnnfiunofaet
`lhepnlenIinlincrunedriIk.'l'|umuningandevoning
`donsdorinthmrehhneqnaliiuineandndinniiatrahinol
`thndru¢InouefnqiiuitlyI.hnI:ivinedailydoeIrIiO.neiiu-
`alIymnh'aadifiIu|uiIIIumIIo(naCI.INlCALl’HAR—
`MAOOLOGY).
`Juunlahlhilh: 'l1ininoofNAl'll0SYNSnopenownnl-
`li1I|IiirnioreI!exIh|edo|etItra¢lm.lnpediatricputieinI:,
`douuoffi niykddayllniluoeil plasninkvehdnapunm
`siinilarlantlinseoeeninndiilhlakingstllingofnprnnen
`(sseCl.lNlCALPl-IARIACOLDGY).
`The ruoonmended Inhl daily (Inns in npplnximateb 10
`mjkggiinnintanotividnddooeslimfiindkzpvabuiien
`l|ay)(IeoD08AGEANDADIlINl8l'RA’l'!0N).
`INIDICATIOIBANDUSAGI
`Nqixonn u NAPROSYN, EC-NAPROSYN. ANAPROX,
`ANAHl0XDScrNAPlKBYNSiupui-'miueind'n=diedI’ot
`1lIel.renmeI|tnfrIIeinnaOiIillIrtIIritiI,oe|eouthriIin,nnhy«
`
`epioiotonynndlilerineoinnlruefionpninantlclysmainrrlien.
`0noatofpIinrelinfcanheginwiIhh1hanrinpalisnIstnk-
`inzmwoxmudwithinaominntuinpafimtsukmg
`nnpmnauodiiun AnaIaaaicdTeuwud'ioIrnhysuchinn-
`ulmuruluctiunnfpaininlenlitysnnregincnnneilipoin
`IuIIoI'Ioonl,bcmuninnun|htroofpn1.i¢rlhIequ11ngIrl-
`dil.ionnlanalp-icuedien¢im,niddclayintiInehnno¢li-
`caI.ion.‘l1:oanakceicefed.luahouifiiundhlntforupIo
`l2hnun.
`Naminmnnyheuaednklyinmmflmbmwifligoldnh
`andIIn'oortimshmila;however.inoII|1Iolleddinl:a|tnaln.
`wlunnfildtolhereginunofpafiaihmwivingoulfiannm
`oid:,it¢l'nlnotappurtocaiIaegIenta-ilnprovenentover
`flIntIeenvnthciirh'eolIaInulnaIone.Whn¢hnrnnpI'unInIiu
`n'suniil-opnni('efl7eclhunothe:nndoquAhIynuul'iotl.
`Whnnatldedlotliemgiinniofpationbnouivingpldnlta.
`nnpzumdidrenihingruhriinprnvsniontltsuinnoow
`hnalionwillualieylntnianotncoinmendedheenuaatheu
`-evidenoetliutuxgiinninaeasuflunhdunetimof
`nnpnxen and dnhuoinuhquntehdelnonatlnto that
`III]II1I!£I| aiidaspirinprndncegmaiieriinprovenentaver
`IIutncIiwnd' wi.IIaspinn' uluir_lnad(lihuI",IlWiI’]IOClEl'
`NSAlDo.tli¢¢oInIn'uotinnninynn!¢in|ndiorfnqumi:yd'
`ndvetusvenhthundanonutmlietlirentherprodndalono.
`ln"CrblooII|ouIntlusl.loIoopys1mlieuwlIhiun'n|lvo|-
`nnteuI,dnlyadmiIiItI'Ihmd'lll)0IIgoI'nnplIimiu
`1000lIgofNAPlllBYN(nnpmxen)otll00Ingof
`ANAPI¢0X(naprnra:siiiiinni)hIshsendcnuistntedIo
`nun animal]; xi;-nificnntly leu uutrlchleedingand
`eninonthui3260in¢ofupmn.
`Thine 6-week. dmiile-blind,
`innltimnhr studies with
`E(‘rNAPfl(SYN(napronn)(315ir600nighid,n-aalilmd
`NAPB0SYN(376a-600n¢|iid,n219)Iremoonducted
`comparing H}-NAPROSYNIMINAPROSYN, indilling
`assrlieumatoitlarthiitnuidoutsouthriiinpatientawlio
`hndnneenthido1yoflBAllJ-relnudGIsy-pIIinn'lhue
`studieoindinudlhnl BC-NAP'ROSYNamINAPR(BYN
`shuuednonpnfimntdifluenceoinfiencyornfityuid
`hadIimilnrpron|uu:ed'minor0lnmpIninta.IndivitIul
`pini:nIs.lwuever,nnyfinduieiinnulnlIinpreli:mh|oh
`thoolliu-.
`Five
`hundred
`and
`lifliy-Ilimee
`patient:
`received
`EC-NAPROSYN during ling-Inn: iipenlahel trinll (innn
`lenglhoftmifinnntwu l59dayI) 'lhn-nhnfilrclinicnllr
`dingnooadpopticiilcennndclhleedowenainiluhowhnl
`hanheunhistai-iullyrupurteilfiirlong-terinNSAlDi-o.
` WD%E
`Suspension.
`Although
`NAPROSYN.
`NAPIIOSYN
`BC-NAPROSYN, ANAPROX and ANAPIIOX [)8 all unau-
`lutcintheplumaunnpnuen,theyhavepIiannaoolund.it
`diEeronnuthntninynfiedouetoI'action.0nnetol'puinm-
`lief can begin within 30 minutes in patients taking
`napmunsodlumnnllwithlnlliourlnpnuentstnkiiig
`napvnx:n.B¢anseE0-!lAPlK)SYNdissolvesiiithesinall
`intedinonthienhaniIithn:tnmacli.tl'¢nhsorpIiono(t.Iie
`dnigndelayedwmpnndlotlleaflwrnnprunniirnlult
`lioIu(seeCLlNICALl’HAEAOOL(XiY).
`Tlinncnmniemlndltrnkgyfotlnitinlingthanyyilln
`dmnuenfiumulnhnalidndartuigihuhkdyhoheefio
`tIvefia|-thnpIt’2dnndlhmadjuotIhedoaugeIIimaloiIoh-
`s¢nntionofhenelitan1lIoradvu'neevenh.Alnwerdme
`sImn|dheoonuiienedinpnuentnIviIhrI:nalorhepa:icini-
`poirnientwnieldarlypafuntslsan PRECAUTIONS).
`
`uNAPR08YNSu:penIiininnooininended
`N
`juvenIlorI:eIImdAIdnrtlI'itiIinoIderInoh¢ainlhunnxi-
`mundulaalenhlityhaedmflnpdiauthwudit
`NnptoiinnuNAPIl0SYN,ANAPROX.ANAl’ROX$1nd
`NAPROSYN3napenoionnmnlnoin¢l:cat¢¢lforlhalnnt-
`niAntoltAnfinihI.hurnit'n,aciil:epIt.nntlI'orthninannge-
`nienlofpniuandprimnxyilyunenoi-r|:ea.BC-NAPll0S‘lN
`innotreoommendoilfu-iiitialuealmcnlofaciiupninhe
`rauntlienhoorph'uuofnapmmniAdaIIyIdwnIparudlod>-
`Iorptian from ofinr m products (see
`CLINICAL PHARMACOLOGY nnd DOSAGE AND A!)-
`IHNISPIIIKITON).
`OOIITBAINDICKITGIS
`All mpluelipmtlndlnnoonhnindiuletl in puieunwho
`hnnhndnllergieruachnnxuipnon-iixinnuwellutoovuk
`llneuununprodndaemihiniiignnprnlon Ili-nhneontnn
`indicnhdinphenuinwlunupix-'morotlurnonduuida|
`afl nhmu drugs indium Ihnsyndmnnenf
`nathinn. rliinifisund nunlpolypo. Bmhtypisofrucxiinu
`hmefliepiihntialofheingfnlnl Anafliyhdoiilluehonsh
`nnpto:nn.whnthsi_-d'thnnieal|ei-|,ictypeorIl:epharmn-
`oologieii!'noyiiaatic(e¢. nspirinhypn-Iunitivity syndmne)
`typ¢,imnlyIriihuit.nlwnyuoeairinpati.-Ilnwilhnhnurn
`liiuhryofuudimoetimn.‘l|inIiim,canfiilqueohuiingJ
`puti:nuiirmidnlhin;oosu|hmn.nunlpolypI.urtienrin
`anilhypousiiui nsuicialaed with nonnhniidnl Iflfi-II|.Ifl-
`innurythIphefwesuzIinglhunpyinipwl.anLInad:l.i-
`l.lon,ifmnd1syinptnniIoei:iirdurin¢thernpy.tmnI.Iinnt
`shaulllhcdiaoontnned.
`WAININGS
`lfilof(.illkOnlhn.UllfifllIIlPclkrnllonIvih$AD
`Ilorapy: Su-ion gaaroinhnfiml Iuxinty suehu blend-
`in¢,uloexaiiuiundp¢r|7uuI1inicnnoocuratuiyIiine,with
`nrI:ithml:wnIningsyn1>tiIns.inpaIientttleoutlcluIini-
`i:allywithN8AlDIhenpy.Alunughmmn-nppergulnin-
`¢cshnnlproI>lemu,uicliu¢lyIpopcin,anmnniin,nuinlly
`denlopingearly in Ih¢rap_y,pIiyn'i:imI flinuld reuiunnlml
`liirulirtnliinanadhlesdiiigin pntlmbtmnladchronically
`wifliNSAllhe'veniII¢hanhse||oniil'pIeviousGlund.synp-
`tannin. In patienls observed in cllllltll trials ofsevernl
`iniinIIIh)2yearI’lli|rnIinn,sym1noniaticuppcrGIu|on-s,
`
`.
`ulolionfiludicaloihhuieinouicluliveooncuning
`ntlveiiakofvnrini-NSAIDoineauning-uchrncliona
`I-ligh¢|oseso{myllSAlD]ixIi|:nhlyuin'yngnaln-xieko
`l.hemIeu:liiniI.nltlimIglIeontlnIhdc|inii:|luuhslwIvnI:
`thisdontuhtmmntusulnmnsideiingflnnuifml
`auvnlyInmediisa:(Ivil.liintherseuniniiindod¢lnsagerui¢ll
`nilfieientheneitslunnldheaihcipatedhofiltfliepiien
`tinl'in:ieu¢drislof0Iuim-fly.
`PIIICAIHIONS
`Gaunt
`uarnoxeu-eomanmornonucissuu
`$HAFfl$VM AWI@L$APMXN
`NMMSVII SUSPENSION.
`ILEVEO'. All) OTIE
`NAIIIOXEfll'KIIlW'I'89|0II.DlKITEUClI®l
`I'I'ANTLY$I:ETHEVAl.LG|¢Il.KI'EH'l'IEPI.ASIlAN
`Tlfllfliixfillllfi.
`lfthestuiddooeiarodnoodordiminimdduiniglliu-up:
`diesoemidllougeshonldheiuliwsilslnwlyandthnpa
`tienholluuldheolilervetldoulyiirnnyevidcnonofadvela
`eEecu,niduilingndn|inlinsIIficiencyIrinleueerhatinn1
`syiqiloncofutlil-Ilia
`Pufimbwifliinilialhonnglnhilvnluuoflflgramaarbl
`whoaietoreouivuliiuig-tmmthonpy-hmildhuvelixogli
`Iinvdusdeterniinotlpuindnally.
`TIieumpyrui:nidanti—inllaInmmn-yuctivuluoflludru
`nayi:dnoeinernndinflainninIiiin.thin¢|imnIdilngth:i
`' yudiagnniicsigtuiiidetuxingounpliufiondpn
`anniediioIiinfa:tiIiu,noIiinInnn|loi'ypaInfnlooInl'i|on:
`Beeainuofndvemeeye flndinpmaninnlltudiuwil
`dnipoflhiadan,iti:neon:nendndIlinto|iilhalniicoIni
`iuhoenniedoutiinnynhnngecn-diuurhunisoinviuiono
`um.
`
`Inrydrnp,liing—terinodliini3InLiinio(iiqunnnInan
`mnkhureeuladmmnnlplpflnryneuuhndoflizrd
`nmmulnenalpnfisolo¢y.InhnInnnn,theIehi!vohunrepo|1
`olusnlninoerulzitinlneplu-itis_hernaI1irr|u,pniunur'nan
`oeusionallynoplnnticoyndwnouaooinhod-ithuapunnei
`ninrhtnil
`Aasooiilliitniofmnnlunidtyhmhemleailiipntlon
`hliiiigna]imxcnnwelluiithei-iioimexoidnlanfi-infln
`malnrydruu.I|pIhenlswith]lemnalunIIifiuin|udiI
`nuntlnctioIiinrunnlh|oodflmvu'h|oodvolnna,wl|auIl
`Ienalplostnglnndinshavennpporhvemleinthnluml
`n|nned'tennlpoIfiuion,atlnIininh-niimofnmnioumicl
`null-mflniniiintorydrugmnycoinsndonodopuidntudu
`diininprootnglmuiinfin-nntionnndpuipifdnuveiiren
`deoonipelnauin Pnfienuatgruteolrlnkuftliionnctii
`
`tinuatinnofnimatauidalanliainflnmnnhrytliernpyinty
`icallyfiilluwedhytearvcryhotliojilntrelhlnlltinle.
`Nqilnxuianditnnintaluolilnnanoliininnhdpninunlyl
`|lw|LidnoyI;llwlefiile,Il:e¢IrngdunIli*lheunedwil.heIulii
`inpalienlsIntha|¢nlflcantIyiiqiIindnunlfuncIion.ai
`anonuadvisedilnheaepatienllcantiuislnuldheuaod
`tlicdrlqilgivuitopalieiitnwithaeatiiiledcnrmce
`lestlinnzonlilnimmhemusenucumnlationofnnprnn
`nehhdituliaslieenseoninmdipatients.
`
`withdacxuaailornhnm-:ulpInnnnpmuino(nI:unin)i
`¢lui:ntheIntnlplunInI:onoemlntiiinofnupmx¢n.hiILt'
`plunnoonosnlrationofiinhoiind napnixznioinciemi
`Cmlioninadvisediliuihiglidouuueiemiirulundsin
`Itliilllientofcliingenayhereiyiiirediiithenpatiaih.
`isprnclenthusefliolnwutellhctivedooe.
`Studimindicnlnthntnlllinuglilalnlplumnmuoenlntion
`nnpnmen-In¢hnn¢tl,tlieunhoundpln:mnfrndinn
`naiplnxenuincmnsedinllirdderly Cnitinnisntlvil
`whenhlglidnsesuuruqirindandnmneadiiutmentoldi
`agnayhereiluilsiiinelclu-Iypni.IeIil.s.AsIvitliotlunhi
`usedmlheellerlxituptuduntauudiehuentelsdi
`dose.
`Mopnieiuncllom Aswithollm-Iiiniaoeroiilnlnnh-nln
`Inulalydncghnlvlfllilneelevalionnofnnoorlnoralit
`Oaestumnyon:nrinuptol5’bofpahenta.'l'lisnenhIienu
`tielmaypmgxuqninyrunuinenenliallyiinchnnged.
`mnyhotr:nsIeIItVlIhuinlinIelthrnpy.'lIi¢S}l"l'(Al
`
`i
`
`
`
`
`
`SSH!ifiiaigsi.-.-Mn:5i.=:5§.!-7'7!fil:.'F:.'P8dl?8ui-5.:-r-r-r?'I"H'l"l'|i'fi
`
`
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`

`
`ANAI-‘BOX
`ANAPROX D8
`
`ROCHE LABORATORIES/2633
`PRODUCT INFORMATION
`
`NAPROSYN
`250 mg
`twice daily
`test is probably the most sensitive indicator ofhver dysfunc-
`or 376 mg
`twice daily
`tion. Meaningful (3 times the upper limit of normal) eleva-
`or 500 mg
`twice daily
`tions of S6?!‘ or SGUI‘ (AST) occurred in controlled clinical
`215 nu
`twice daily
`trials in less than 1% of patients. A patient with symptoms
`(napruxsn 260 mg with 25 mg sodium)
`andlor signs suggesting liver dysfunction or in whom an ab-
`550 mg
`twice daily
`normal liver test has occurred, should be evaluated hr evi-
`(napr-oxen 5(1) mg with 50 mg sodium)
`densa of the development of more severe hepatic reaction
`twice daily
`250 mg (10 roll! tsp)
`while on therapy with naprosen. Severe hepatic reactions.
`twice daily
`or 376 mg (15 mil}! tap)
`including jaundice and cases of fatal hepatitis, have been
`twice daily
`or 600 mg (20 mils. tsp)
`reported with napmxen as with other nonsteroidal anti-
`EC-NAPROSYN
`twice daily
`376 mg
`inilammatory drugs. Although such reactions are rare, if ab-
`
`or 500 mg twice daily
`normal liver tests persist or worsen, if clinical signs and
`symptom consistent with liver disease develop. or if sys-
`temic manifestations occur (eg, sosinophilis, rash, ete.),
`cardiovascular: edema‘, dyimnsa*. palpitations
`naprorren be temporarily discontinued 72 hours before adre-
`General: thirst
`nal flinotion tests are performed if the Porter-Silber test is
`naproxen should be discontinued.
`to be used.
`Fluld Iletantion andErlama: Peripheral edema has been
`‘Incidence of reported reaction between 3% and 9%. Those
`observed in some patients receiving naproson. Since each
`reactions occurring in lam than 3% ofthe patients are un-
`Napmxsn may interfere with some urinary assays of 6-hy-
`marked.
`ANAPROX or ANAPROX D3 tablet contains 25 mg or 60 mg
`droxy indoleacstic acid (El-IIAA).
`Incidence less than 1% (Probable Causal Relationship):
`ofsodium (about 1 mile per each 250 mg of napruxsn), and
`carcinogenesis: A 2-year study was performed in rain to
`each teaspoonful oi'NAPli0SYN Suspension contains 39 mg
`evaluate the carcinogenic potential ofnapruxen at rat doses
`The following adverse reactions were reported less fre-
`(about I 5 mEq per each 125 mgofnaproiren) ofsodium. this
`quently than 1% during controlled clinical trials and
`of 0. 16 and 24 rridkdday (50, 100 and 160 main’). 'I1is
`should be considered in patients whose overall intalre of so-
`maximum dose used was 0.28 times the systemic exposure
`through voluntary reports since insrlceting. These reactions
`to humans at the recommended dose. No evidence cftumor-
`dium must be sovcrely restricted For those reasons,
`observed through voluntary reporting since marketing are
`italicised.
`ANAPROX. ANAPROX D8 and NAPROSYN Suspension
`igenicity was found.
`Gsstrolntaatlnat abnormal liver /imctwn tests, colitis, gas-
`should be used with caution in patients with fluid retention,
`Pregnancy: Tbmrogenic Efiicts: Pregnancy category
`trointestinal bleeding aodlor perforation,
`liomolemsara,
`hypertension or heart failure.
`B. Reproduction studies have been performed in rats at 20
`in NAPROSYN,
`Information for Patients: Naproxen,
`jaundice, pancreatitis, melena. vomiting
`rndlrgldsy (125 mg/m’Iday. 0.23 times the human systemic
`EC-NAPROSYN, ANAPROX. ANAPROX DS
`and
`