AMN1065
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`EDITION
`
`55
`2001
`PHYSCANS'
`DESK
`REFERENCE®
`
`Senior Associate Editor: Lori Murray
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`
`Senior Vice President, Directory Services: Paul Walsh
`Vice President, Sales and Marketing: Dikran N. Barsamian
`National Sales Manager, Custom Sales: Anthony Sorce
`Senior Account Manager: Frank Karkowsky
`Account Managers:
`Marion Gray, RPh
`Lawrence C. Keary
`Suzanne E. Yarrow, RN
`National Sales Manager, Medical Economics Trade Sales:
`Bill Gaffney
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`Vice President, Clinical Communications and
`New Business Development: Mukesh Mehta, RPh
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`Manager, Drug Information Services: Thomas Fleming, RPh
`Drug Information Specialists: Maria Deutsch, MS, PharmD, CDE;
`Christine Wyble, PharmD
`Editor, Directory Services: David W. Sitton
`Project Manager: Edward P. Connor
`MEDICAL ECONOMICS Copyright© 2001 and published by Medical Economics Company, Inc. at Montvale, NJ 07645-1742. All rights reserved. None of
`the content of this publication may be reproduced , stored in a retrieval system, resold, redistributed, or transmitted in any form or
`by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of the publisher.
`PHYSICIANS' DESK REFERENCE®, PDR~. Pocket PDR" , The POR® Family Guide to Prescription Drugs• , The PO~ Family
`THOMSON HEALTHCARE
`Guide to Women's Health and Prescription Drugs• , and The PDR° Family Guide to Nutrition and Health" are registered trademarks used herein under license. PDR for
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`
`ISBN: 1-56363-330-2
`
`AMN1065
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`PRODUCT INFORMATION
`
`stool, thereby decreasing·intralunrinal pressure and strain-
`ing, and speeding colonic transit in constipated patients.
`INDICATIONS
`Metamucil is indicated for the treatment of occasional con-
`stipation, and when recommended by_ .a physician, for
`chronic constipation and constipation associated with irri-
`table. bo~~l syndromB, diverticulosis, h~!lJ.orrhoids, conva-
`lescence, senility and pregnancY- Pregnancy: Category B. If
`considering use of Metamucil as part of a cholesterol-lower-
`ing program; see Metamucil Dietary Fiber Supplement in
`Dietary Supplement Section.
`CONTRAINDICATIONS
`Intestinal ob~truction, fecal impaction, allergy to anY com;
`ponent. ·-
`· ·
`·
`·
`WARNINGS
`Patients are advised they· should consult-a doctor before us-
`ing this product if they-have abdominal pain; nausea; vom-
`iting or rectal bleeding, if they have noticed a·-sudden
`change in bowel habits-that persists over'a period"of-two
`weeks, or if they' are considering use of this product as part
`of a cholesterol-lowering program. Patients are advised to
`consult a physician if constipation persists for longer thlin
`one week; as'this maylie a sign of serious medical condition.
`Patients are cautioned that taking this'·product without ad'
`equate ·fluid may cause it to' swell and block the throat.or
`esophagus and niay cause choking. Cfhey should r\ot take
`the product if they have difficulty in swallowing, lfthey ex-
`perience'chest pain, vomiting, or difficulty in swallowing or
`breathing after takin!i''this product,.they are-advised to
`seek immediate medical attentionr·Psjrllium ·products may
`cause- allergic reaction in people sensitiVe to inhaled-'or in'
`gested psyllium. Keep out of the reach of children. In case of
`accidental overdose, seek professional assistance or contact
`a poison control center i:rrnhediately.- ·_'
`P~CAUTii:>N
`Notice to Health Care Professional: To Aiinimize the poten-
`tial for allergic reacti011, health care professionals who fre'
`quently dispense powderedpsyl)iwn·products should avoid
`inh:iling airborne dust while. dispensirig-these products.
`Handliog. and Dispensing:_'fu minimize: generating airb,orne
`dust, spoon product from the canister-into a glass acc0rdirig
`to-label directions ..
`DOSAGE AND ADMINISTRATION
`The ','Suai adult dos;,ge is one r~unded teaspodn, or, taple-
`spoon, dependirig .on the product version. some versions are
`available in single-dose packets. For chlldren {6 _t'o l2 ye_ars
`old) use \1 the adult dose; for children W>ner 6, consUlt a
`doCtor. The appropriate dose shoUld be niliied 'wit}) 8 ,oz. of
`liquid (e.g" cool _water, :fiuit juice, milk) follpwirig the label
`instructiop;~. Metam11cil Fiber, Wafers sh_o":ld.be co)lsumed
`with 8 oz .. ofliquid: The product (ch~dor: adult dose) should
`be.taken with at least 8 oz, (a full glass) of water or .other
`fluid. Taking this product with~ut e,nou'gi)Hq~ld !llay ca.1,1.se
`choking (see warniltgs). Metamritil can. be taken onii to
`three times per day, dependirig on the need and response. It
`may require continued use for 2 to 3 days to proVide optiinal
`benefit. Generally produces effect in--12.::72 hours. _
`_ '
`Laxatives, htcludirig bulk fibers, may affect how vrell other
`medicines Y,ork. If you are taking a pr~sc]iption medicine
`by mouth, ·take this product at least 2. hours b~fore or 2
`hours after the prescribed medicin~. As your body adjust~-to
`increased fiber intake, you may e,.P-;;rience changes in bowel
`habits or minor bloating.
`· ·
`·
`:..,
`HOW SUPPLIED
`Powder: canisters imd cartons of single-dose packets. Wa-
`fers: cartons of single dose packets. (See Table 1)
`[See table at bottom of previous page]
`
`PEDIATRIC VICKS® 44e
`COUGH & CHEST CONGESTION RELIEF
`Cough Suppressant/Expectorant: --
`
`(Se~ PDR For NonprescriptiQn Drugs.)
`
`PEDIATRIC VICKS® 44m
`COUGH & COLD RELIEF
`Cough Sup'jnessant/Nasal
`Dec~llgestant/ Antihistamine
`(See PDR For Nonprescription Drugs.)_
`
`OTC
`
`OTC
`
`PEPTO-I;IISMOL®
`ORIGINAL LIQUID,
`ORIGINAL AND CHERRY TABLETS
`.. -. •:
`AND EASY-TO-SWALLOW CAPLETS
`For upset stomach; indigestion, diarrhea, heartburn
`and nausea.
`•
`'· --~· ·
`
`OTC
`
`Multi-symptom-Pepto-Bismol contains: bismuth ;s'ubsalicy-
`late and is the ouly leadirig OTC stomach remedy clinically
`proven effective for both upper and lower Gl syniptoi:ns.
`Pepto-Bismol is in more households than any other stomach
`remedy, making· it a convenient recommendation ·with a·
`name -your patients will know. It has-been 'clinically proven
`in double-blind placebo-controlled trials for r-elief' of upset
`stomach symptoms and diarrhea.
`·
`
`DESCRIPTION
`Each tablespoon (15 ml) of Pepto-Bismol Liquid· contains
`262 mg bismuth subsalicylate. Each tablespoonful of liquid-
`contains a total of 130 mg non-aspirin silicylate: Pepto:
`Bismolliquid contains no sugar and is low in ·sodiilln (less
`than 5 mg/tablespoonful). Ina~tive irigredients: benzoic acid,
`D&C Red No. 22, D&C Red No'.'28, fla~or, magnesium alu-
`minum silicate, methylcellulose, saccharin sodium, salicylic
`acid, sodium salicylate, sorbic acid and water.
`Each Pepto-Bismol Tablet contains 262•-irig bismuth sullsa-
`licylate. Each tablet contains a total of 102 mg non-aspirio
`salicylate (99 mg uon-aspirin salicylate for Cherry). Pepto-
`Bismol tablets contain no sugar and are very low in sodium
`(less than 2 mg/tablet). Inactive ingredients include: adipic
`acid (in Cherry ouly), calcium carbonate, D&C Red· No, 27,
`FD&C Red No. 40 (in Cherry only), flavors, magnesium
`stearate, mannitol, povidone, saccharin sodium arid talc:
`Each Pepto-Bismol Caplet contains 262 mg bismuth subsa-
`licylate. Each caplet contains a total of 99 mg non-aspirin
`salicylate. Caplets contain no sugar and are low in sodium
`(less than 3 mg/caplet). Inactive ingredients include: cal-
`cium carbonate, D&C Red. No. 27; magnesium stearate,
`mannitol, microcrystalline cellulose, polysorbate 80, povi-
`done, silicon dioxide,_ and s?dium starch' !flycolate.
`-
`INDICATIONS
`Pepto-Bismol controls diarrhea within 24 hours, relieving
`associated abdominal cramps; soothes heartburn and indi-
`gestion without constipating; and relieves nausea.and upset
`stomach.
`-
`ACTIONS
`For upset stomach symptoms_ (i,e., indigestion,. heartburn,
`nausea and fullness caused 'J)y over-indulgence), the. actJire
`ingredient is b_elieved to work via a topical ejfecCon the
`stomach mucosa. For diarrhea, it is believed. to work by sev-
`eral mechanisms in the gastrointestinal tract, illcludirig:' 1)
`normalizing fluid movement via an antisecretory mecha-
`nism, 2) binding bacterial toxins and 3) antimicrobial activ;
`ity.
`,.
`•,_
`--·
`."
`'·:
`':
`WARNINGS
`Children and teenagers who have or are'tecovering from··
`chicken pox or flu should not use this medicine• -to treat- nau-
`sea or vomiting. If nausea or vomiting.<is .present, patient~
`are advised to consult a doctor because this could--be an
`early sign of Reye syndrome, a rare but serious illness .. ·
`This product contains non-aspirin salicylates. If taken with
`aspirin and ringing in the ea.rs occurs, discontinue use. This
`product does not co~tain aspirin; but should riot be admiii.-
`istered- to thbse patients who h~ve a knowri allergy to aspi-
`rin or non-aspirin s'alicylates as an adverse reaction may oc-
`cur. Ca'Utio;;_ is advised in the administration 't0 patients
`taking ,medi~aiioti for anticoagulation, di'!:betes and gout _
`I(di,arrhea is' accolifpanied by a high.fev~r or continue~
`nioni tliari'2 day's, patients are advisea to consUlt-a physl,
`cian. As with any drug, caution is advised iri the adniinis-
`tration to pregnant or nursing women,
`Keep all medicine out of the reach of children.
`Note: This medication may cause a temporary and harniless
`darkening of the tongue and/or stool. Stool darkening.
`should not be confused with melena.
`OVERDOSAGE
`In case of overdose, patients are advised to contacl a physi-
`cian or Poison Conti-ol--Cimter. Emesis' induced by~ipecac
`syrup is indicated in large 'irigestioM provided jpecac·c.m be
`administered withih orie hour of ingestion. 'Activated char-
`co'al should be administered after gastric emptyiog. Pa:
`tients should be evaluated' for sigris imd symptoms of sali,
`cy1ate toxicity.
`· _
`· " · ·
`"
`DOSAGE AND ADMINIS~RATION
`Liquid: Shake well before. using.
`Adults~· , -2 tablespoonsful
`' · . · .
`(1 dose cup, 30-ml)
`Children (according to age)-
`9-12 yrs. - 1 tablespoonful
`('J. dose, cup,_ 15 ml)
`2 teaspoonsful
`('fa dose cup, ·10 ml)
`1 teaspoonful
`·
`('fs dose cup, 5 ml)
`Repeat dosage every 'f.to 1 hoill, if needed, to a maximum
`of 8 doses in a 24-hour period. Drink plenty of clear flllids to
`help prevent dehydration which may accompany diarrhea.
`For children under 3 years of age, consult a physician.
`Tablets:
`Adults~ Two tablets
`Children (accordirig'to .age)-
`9-12 .yrs.
`--1,tablet
`. "fa tablet
`6--o-9 yrs:
`'1, tablet
`3-6 yrs.
`Chew or dissolve'in:mouth. -Repeat every "f. to 1 hour as
`needed, to a maXimum of 8 'doses in a 24-h.our period. Drink ·-_-
`plenty of clead!uids to h~lp pieven:t 'dehydration, which.
`may accompariy diarrhea. For. children under 3 years of age;
`consult a physician.
`Caplets:
`' Adults~ Two caplets
`Children (according to age)-
`9~ 12 yrs,
`1 aaplet
`-· 6-9 yrs.
`"fa caplet
`1/ 3 caplet
`3-6 yrs.
`
`6-9 yrs.
`
`3-6 yrs.
`
`PROCTER & GAMBLE/2663
`
`Swallow capl.,tjs) with water, .do not chew. Repeat every
`'f. to 1 hour as needed, to a maximum of 8 doses in a 24-
`hour period. Drink plenty of clear fluids to help prevent de-
`hydration, which may accompany diarrhea. For.childreB uri-
`der 3 years of age, consult a physician..
`HOW SUPPLIED
`Pepto-Bismol Liquid is available in: 4, 8, 12, and 16 FL OZ ..
`bottles. Pepto-Bismol Tablets are pink, round, chewable tab- ·
`lets imprinted with a debossed triangle and "Pepto-Bismol"
`on one side. Tablets are available in: •boxeso- of 30 and 48.
`Caplets are .available inhottles' of 24_ and 40. Caplets are
`imprinted with "Pepto-Bismol" on OJ18 s!~~--
`
`ore
`
`PEPTO-BISMOL®
`MAXIMUM STRENGTH LIQUID
`For. upset stomachiindigestion,
`diarrhea, heartburn and nausea.
`Multi-symptom Pepto-Bis111ol contain~ bi~muth subsall~~­
`late and is the ouly leading OTC stomach remedy clinically
`proven effective for ·both upper--and lower GI symptoms.
`Pepto-Bismol is in more households than any other stomach
`remedy, making it a convenient recommendation with a
`name your patients will know. It has been clinically-proven
`in double-blind plficebo-controlled trials for relief of upset
`stomach symptoms and diarrhea.
`DESCRIPTION
`Each tablespoonful (15 ml) of Maximum Strength Pepto-
`Bismol Liquid contains 525 nig bismuth subsalicylate (236
`mg non-aspirin salicyJate). Maximum Strength Pepto-Bis-
`mol Liquid contains no sugar and is low in sodium (less
`thari 5 mg/tablespoonful). Inactive ingredients include: ben-
`zoic acid, D&C Red No. 22, D&C Red No. 28, flavor, maghe•
`sium alunrinum silicate, -methylcellulose; saccharin sodium,
`salicylic acid, sodium salicylate, sorbic acid and water.
`INDICATIONS
`Maximum Strength Pepto-Bismol soothes upset stomach
`and indigestion without constipating; controls diarrhea
`within 24 hours, relieving associated abdominal cramp,<;;
`arid relieves heartburn an!fnausea.
`-
`-·• - ·
`ACTIONS
`For upset stomach symptoms (i.e. indigestion, heartburn,
`nausea and fullness caused by ovei--illdulgence), the aCtive
`ingredient is believed to work via a topical effect on the
`stomach mucosa. For diarrhea, it is believed to work by sev-
`er:il mechanisms in the gastrointestinal tract, inc1udirig: 1)
`normalizing-fluid movement via-an antisecretoty mecha--.
`nism, 2) binding bacterial toxins, and'3) antimicrobial activ-
`ity.
`WARNINGS
`Children and teenagers who have or are :recovering from
`chicken pox or flu should not use this medicine to treat nau·
`sea' or vomiting. If nausea or -vomiting is present, patients
`are advised to consult a doctor because tills could be an
`early sign ofReye syndrome, a rare but seriou_si]lness. ·
`·
`This product contains non-aspiiin ii~licylate~. If taken-with
`aspirin and ringing in the ears occurs, discontinue use. This
`product does not contain aspirio, but.should not be adruio-
`istered to those patients who have a 'known allergy to aspi-
`rin or other non-aspirio salicylates as an adverse reaction
`may occur. Caution is advised in the adroinistration to pa-
`tients taking medication- for ariticoagillation, diabetes arid ..
`gout.
`' ·
`..
`·
`'
`-
`If diarrhea is accompanied by a high f~ver or continues
`more than ·2 days, patients-are advised to consult a physi-
`cian. As with any drug, caiition:is-advised: in the adminis-
`'
`tration· to pregnant or nursing women.:
`Keep all medicine out of the reach of children.
`Note: This medication may cause a temporary and. harjll-
`less darkening of the tongne. and/or- stooL Stool d!u-kening
`should not be confused with melena.
`OVERDOSAGE
`In case of overdose, patients are advised to contact a-physk
`cian or Poison Control Center. Emesis induced by ipecac
`syrup is indicated in large ingestions provided ipecac• can be
`adroiriistered within one hour of ingestiou. Activated char-
`coal should be administered after gastric emptying. Pa-
`tients should be evaluated for signs and symptoms of sali-
`cylate toxicity.
`DOSAGE AND ADMINISTRA.TION
`Shake well before using.'
`Adults-
`2 tablespoonsful
`(1 dose cup, 30 ml)
`Children (according to age)-.-
`9-12 yrs.
`1 tabiespoonful
`('I, dose cup, 15 ml)
`2 teaspoonsful
`('fa dose cup, 10 ml)
`1 teaspoQ_nful
`('is dose cup, 5 ml)
`Repeat dosage every hour, if needed, to -a· maximum of 4
`doses in a 24-hour period. Drink pl<\nty of clear fluids to
`help prevent dehydration, which may accompany dimhea.
`
`6-9 yrs.
`
`3-6 yrs.
`
`Continued on next page
`
`Consult 2001 PDR® supplements and future.editions for revisions
`
`AMN1065
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`3052/SMITHKLINE BEECHAM CONSUMER
`
`Denavir-Cont.
`
`CAUTION: . Federal' law prohibits dispensing without pre-
`scription.
`·
`Comments or questions? Call toll-frSe 1-S00-320-6022.
`Manufactured in Cidra, PR by- Sn\ithKiine Beecham
`Pharmaceuticals, for SmithKiine ·Beecham Consumer
`Healthcare, L.P:, Pittsburgh, PA 15230:· -
`
`OTC -
`
`ECOTRIN
`EntericcCoated Aspirin
`Antiarth_ritic, Antiplatelet
`COMPREHENSIVE PRESCRIBING INFORMATION
`DESCRIPTION
`Ecotrin enteric coa~d aspirio (acetylsalicylic add) tablets
`available in &1mg, 325mg and 500 mg tablets for oral.ad-
`n_iliiistration. The 325 mg an_d 5oo mg tabiets contain the
`following inactive ingredients: Carnuba Wax, Colloidal Sill.
`CO]). Pioxide, FD&CYe!low No.6, Hydroxypropy]Methylcel-
`l)llose, Methacry!icA,cid C_opo]ymer,_Microcrys~@ine,CeUu­
`lose; ;preg~latinize!lStarch, Propylene Glycol, Simetbic_one,
`$odium St?rgh Glycolate, Ste:iric Acid;Talc, Titanium Diox-
`ide, and_],'riethyl.di.trate. The 81 m~ tablets contain:_Car-
`nuba Wix, Corn st;n_.ch, D&C .Yellow No. 10, FD&d Yellow
`;No.,6; HydroJry]J>;opylMethylcell~ose, Mef4accylicA~<! Cp.
`polymer, Microccystalline CellUlose, Propyle!le Glycol, Sin!-
`ethicone, Stearic Acid, Talc and Triethyl Citrate._;.
`. .-;.
`-_
`Aspirin is an o\lorless. whjte, needle-like cry~t,Jline or PO\V"
`dery subsfance .. W!i~i;_.e'Xposed to I)lo~ture. · a,SpiriD."hydro--
`lyzes iz>to sali_cylic and acetie acid~, and gives off 'l.vinegacy,-
`odor. It js highly lipi,d.soluble 'Jl}d' slightly soluble in water.
`CLINICAL PHARMACOLOGY ·-
`M:ei:b~sm._or A,ction: Aspirio is a more potent fuwbitor 6r
`both prostaglandiri s,Ynthesis and piatelet"aggregatioii th8n
`other·salicylic ·a.iid derivatives• The cfuretences in activity
`between aspirio and salicylic acid are thought to be due to
`the acetyl group on the aspirio molecule. This. acetyl group
`is responsible-for the illactivatioil'of cyclo-oxygenase via
`acetylation.
`·
`·
`·
`PHARMACOKINETICS
`.
`Absoiption: -In general, lnunediate retease aspirio is well
`and completely absorbed from the ·gastrointestin,;l (GI)
`tract .. Following absorption, aspirin is .hyUrotyzed to .sali-
`cylic a~id with peak p)a.Sm,a levels of salicylic acid occurring
`within 1-2. hours_ ·of dosing (see Phaqnacokinetics-,-Metab·
`olism): rJ>e.rate of abso'rotion from the_GI tract i~ dependent·
`upon the dosage form, the presence or absence of food, gas-
`tric I>H (the presence or ~bsence of.GI antaclds.or)Uff~r,il'g
`agent,g),, andptller pl>.ysio!o~c f!lctors. Enteric Cl)a1;ed aspi-
`rin products are eqatically absmbed from· the QI tract.~. -.
`Distribution: .Salicylic acid is widely diStibuted-.to .. .:U tis-
`sues and fluids in the bgily .iD.cluding t)le ce:ritr:i.I. h,e.Vo'us
`system (CNS), breast milk, and fetal tissues. The 'highest
`concentratio:ps 3re,f9JJ-n!i jn th~~plas~~. liver, ren.f!l·cortex;
`heart, and lungs.
`, __ . -
`The 'protein- binding- of salicylate is concentration-depim-
`dent, i.e., non-linear. At low concentrations ( < 100 mcg/mL)
`approximately 90 percent of plasma salicylate is boimd to
`albumin, while at higher concentrations (> 400 incglmL),
`only_aboui 75 percent is bound. The early signs ofsalicylic
`·overdose (salicylis}Il), including tinnitus (ringing in the
`ears), occur at plasma con<funtrations approximating· 200
`mcg/mL. Severe toxic effects are associated .with- levels >
`400 mcglmL (See Adverse Reactions and Overdosage.) . -.·
`MetaboliSm: Aspirio is rapidly hydrolyzed.in·the plasma
`to salicylic acid such that pla8ma levels of aspirfu are essen-
`tially .undetectable· 1-2 hours- after dosing. Salicylic acid is
`primarily conjugated in the liver to form salicyluric acid, a ·
`phenolic glucurOnide, an acyl glucuronide, a:nd a number of
`minor metabolites. Salicylic· acid has a plasma half-life of
`approximately 6 hoUr.. Salicylate metabolism is saturable
`an:il total body clearance de'creases-at higher serum concen-
`trations·due·to·the•lirirlted-ability:Ofthe hver to fortn both
`sal1cyluric acid'and phenolic glucilronide:· Followiilg ·tone
`doses (i0~20 · g-r!iros (g)); the plasma:• half-life may be in-
`OreaSed·to over 20-hours.
`.:_'J··'·
`E!irOination: · The- elimination of salicylic- acid follows zero
`otder pbliriliacokinetics; (i.e., the ra.te·of drug elimination is
`constant iii reiation to plasma: ·concentration). Renal excre-
`tion of unchanged drug depends upon urine pH: As urinaiy
`pH rises above 6.5, the renal clearance of free salicylate in-
`creases froni < 5 percent to > 80 ·percent. Alkalinization of
`th&'Ut:ili.e ill'a'key ooncept in 'the ma:riagem!mt of salicylate
`overdose. (See Ovetdosage.i 'Followiri'g'-therapebtic" doses,
`approximately 10 percent is found excreted in thi.'llliD..-" lis
`salicylic acid, 75 perceiii ruhiallcylufic acid; 'as'tliil pheiiolib .
`and acyl glucuronides, respectively. :·.
`--· ,, ___ ,,_._:
`Pharmaco<!ynamics;.- Aspjrin affect~ ,plO.telet aggregatiOI)-
`by ~irreversibly- inhibiting prqsta&:l;indin- c,Yclo-o_xyge_.nas~;
`Thjseffect lasts for th~life of the platele,t 'l".<i p;rev~!'ts;the
`formation of the platelet aggregating factor thromboiane -
`A2. Non-acetylated salicylates do not inJribit tJ!ja ~nzyil;le
`and have no effect on platelet aggregation. At soinewhat
`hlgher doses, aspirin'reyersibly inhibits the:formation of
`prostaglandin 12 (prostacyclin), which is an. arl.!>rial-vasodi,
`lator and inhibits platelet aggregation. 'J.-~·:_.
`•.
`'
`At higher .doses aspirio .is :all effective anti,inflammator.j-
`agent, partially due to inhibition of inflammatory mediators
`via cyclooxygenase inhibition in peripheral tissues. In_ vitro
`
`T
`
`PHYSICIANS' DESK REFERENCE®
`
`studies suggest that other mediators of inflammation may
`Coagolation Abnormalities: ... Even low. doses of aspirio can
`also -be suppressed by aspirio adrainistration, although the
`inhibit platelet function leading to an increase in bleeding
`precise mechanism of action has not been elucidated. It is
`time. This can adversely aJfect_patients-With inherited lhe.
`this non-specific suppression of cyclooxygenase activity in
`mophilia) or acquired (liver dise!l~e or vitaiQin K_deficiency)
`peripheral tissues following large doses that leads to its pri-
`bleeding disorders.
`,
`_. mary side effect of gastric irritation. (See Adverse . Reac-
`GI Side Effects: GI side effects include stomach -pain; heart-
`tions.)
`·
`burn, nausea, vomiting, and gross GI bleeding::AJthough
`CLINICAL STUDiES
`minor upper GI symptoms, ·such as dyspepsia, are common
`and can occur anytime during therapy, physicians shonld
`·'Ischemic Stroke and l'ransient Ischemic Attack (TIA): In
`clinical trials of subjects with TIA's due to fibrin platelet' em-
`remain alert for signs of ulceration and bleedings, •even. in
`boli or ischemic stroke, aspirio has been shown to signifi-
`the absence of preVious GI symptoms. Physicians shonld. in-
`cantly reduce the riSk of the combined endpoint of stroke or
`form patients about the signs and symptoms· of GI side ef-
`death and the'combirieil endpoint ofTIA, stroke, or death by
`fects .and what steps to take if they occur.
`about 13-18-percent.
`Peptic illcer Disease: Patients with a history of aetiv;e p~p;
`Suspect:;Ac]lte Myocardial Infarction·.(MI); In a large;
`tic ulcer disease shonld avoid using aspirin, which'cru;t:ctui§e
`multi-center-study-of aspirin,- streptokinase, and th~ combi-
`gastric mucosal irritation and bleeding.
`''
`'
`nation of aspirin and streptokinase in 17,187 patients with
`::•:
`suspected acute .MI, aspirio treatment produced a 23-per,
`PRECAUTIONS
`cent.reduction in the risk of vascnlar mortality. Aspirio_was
`General
`also-shown to have an additional,b_en~fit in patients given a
`Renal Failure: Avoid aspirio in patients with severe renal
`thrombolytic agent. • . · .
`.
`,
`failtire (glomerular JUtration rate less than 10 mUminute).
`:Prevention of Recurrent MI an,d .. Uns_ta~l~ Angina Pectoris:
`lfepatic Insujliciency: _ Avoid aspirin in pati~p,ts. witli se-
`Th~se inQications '!i-e. supported by the resnlts of si:.i: large,
`vere hepatic ins¢ficiericy.
`-
`·
`-
`randoiniz~~;_.rql)l.j;i.;-~>entet •. · plaeebo·CI/'ltroUa!l_. j;ri!!ls :of. pre-
`Sodium Restricted Diets: Patients,;yrit4 sodium,~e~aining
`dominantly male '!iiist-MI subjects and orie tandoiD.iZ..d pla-
`- states, such as conge~tive h~art fa.Al.!re~~QI':.,:r~n,al failure,
`cebo-controlled study of men with unstable .angina pectOris.
`Aspirio .tharapi in MI supjects :-vas assopiaj;ed with a-Sigpif'
`should avoid sodium:containing buffered aspirio prepara-
`icant reductio.n- (about 20 percent) in the ·risk of the com hi,
`tiOfi\1 b~cause of their high SOdium content .. , :: ... _
`,. -.·
`nation endpomt of subse_quent death aildtor nonfatal iefuf-
`Laboratory Tests: Aspirio has been associitfed With. ele-
`arction in these patients. In aspirio:treated uilstabli,- angma
`vate<] hepatic, e~e's; bi~o\']' ~e.: mfrogen OJ:Ld 'serilm' cre-
`patients the·evaiit.ratewas ~educed to:5 percent from the 10
`atinine, hyperkaleili.ia, · protemrirla, arid prolonged bleeding
`percent ra,f;e,~th~;plaoe}>o gr0up..
`.
`_. ..
`_
`time.· . -~ ' _. ?' ·
`,_
`' -. : ':'_
`·
`·
`· ·': ·.·
`..
`·
`Chrome 'l:ltable :Angina Pectoris: In a ran(\oipized, multi-
`center, doublli-blind 'trial designed to assess the· role of as-
`Dr~Q l~_,eraction~
`.. :
`:
`.-_ . ".
`_ _ _
`.
`. .
`Ailglot~nsm' CQ~~etting E~~e (AC.~) I~bitO~s:_ Th~
`pirin fgr prexention of MI in patients with chronic stable
`hYI>onatreirlic ·and hypotensive ·effect<f of ACE inhibitors
`angiha pectorisi·aspjrii) SignifiCiiri:tly reduced 'the primary .
`may be diminiab~d )>y the C<Jncomitant acb)rinistratiop. of liS:
`combined ejldpofut of iioilfatal MI,:.fataJ··MI, aild'·sudd!m
`pirln due tO its ~~t effect on the renll),'angiotebl!iii co~yer·
`death ·by 34--p~tcent. The secondary ·endpoint for vasculill'
`·r-,·2:·.:-:··-_-·-~ .. -
`:;_,-.·_ ,:_· __
`·:
`· ...
`events (first occurieni:e of )\[I, stroke; or vascular death) was
`si~n·path~vay._
`also significantly-redui:ed (32 percent).
`A<;etazofamide_: Con}/9rient us& qf aspiri_.n;and;a<(<itazola-
`· Revascnlarization.R~ocedures: Most patients who undergo·
`mide can lead to liigb serum Concentrations of' acetazola·
`coron&rJ.artetY r~vascl!l;n'ization procedurea haVE\. already
`mide (and toxicity) due to competition at the renal tubule
`had symptomatic <_:(lronary artery disease for which aspirio
`for Secretion. ·
`·
`·
`·
`is indicated. Similarly. patients wi,th lesions of the caro!id
`Anticoagulant Therapy (Heparfn and Warfarin): Patients .
`bifurcation sill,licient to require carotid endartere<;toiny are
`on anticoagolation ther'I-PY are at .increased risk for bleed-
`likely tO have ... had a precedent event'. Aspirin is recom-
`ing hecause of drug'diug interactions and the effect 0n
`mend~d for pa,tiEmt~ who undergo· rEiVaScul~ation·proce­
`platelets. Aspirin can displace warlarjn from protein bind-
`dures if there is a preexisting: coriditjon for which ·aspirio is
`ing sites, leading to prolongation of both the prothrombin
`already jndicated.
`_
`·
`·
`.
`·'
`..
`·
`·
`·time and the bleeding time. Aspirio can increase the anti-
`Rheumatologic Diseases:
`In clinical studies·in patients
`eoagtilant activity of heparin, increasing bleeiling risk.
`wit)>.' rheumatoid arthritis, juvenile rheumatoid arlhritis,
`a:nkylosing spondylitis "and osteoarthritis, aspirio has· -been
`Anticonvulsants: Salicylate can· displace protein-bound
`shown to be effective m'&introlling various indices·of clinical
`phenytoin ·and valproic acid, leading to a decrease in the to-
`disease-aCtjvity.
`·
`·
`-'" ·
`-
`tal concentration of phenytoin and an increase in serum val-
`proic acid levels.
`·
`NUMAL l'OXICOLOGY.
`Beta Blockers: The hypotensive effects of beta blockers
`The acute oral 50 percent .lethal dose;:in rats is about J.5
`may be diminished by the concomitant administration of as-
`g&:g .and_ in mice 1.1 g/kg. Renal papillary :Qe~rosis.,and de,
`pirio due fo inhibi!;ion _of renal prostaglandins,.l~ading to
`r;reased .. ; urinary .~oncentJ:atii:tg ability occur i:o. roP.ents
`decreaSed reri<ll blpbd flow, 'anrl saJt and.f\uid retenJ;ion. ' .
`chr9l)ically 11dministere<!.high do~es. Dose.-dependent.gas,
`Diuretii:s:' .Tb.e .effectiveness.of iliureties-'ill patients with
`lli)derlYillg renai' or c~J;:o~~~s~ar 4J.sease may. be Climii;.
`tric .m.ucosal injpzy .occws in rats and h_umans. Mammals
`may develop aspirio toxicosis associated With GI symptoms,
`ished by tb.~ .. con~~taiJ.t adinin;istratioil_of.aspirin d11e to
`circnlatory effects, and. central nervous system depressi!)n. ·
`inhibition of renal prostaglandins, 1eading to_ decteased re-
`(See OveJdosage.)
`nal blood flow and salt and fluid retention. .
`.
`INDICATIONS AND USAGE
`Methotrexate: Salicylate ciui uihlbit relial·clearant:e of
`Yascularindi~atjons (Ischemic Stroke, TIA, Acute MI, Pre-
`Jllethotrexate, leading to bone marrow toxiCity, especililly' in
`verition of R.<lcUirent MI, Unstable Angina Pec~oris, ,nd
`the elderly or renal inipaired.
`· -
`~
`Clirouic Stable Angina ~ectori~): A,spirin' is ln\licated tO: (1) Nonsteroidal ·Anti,irijfairinul.toty' Drugs (NSAID's): The
`Reduce the combined risk of death and noufatal stroke fu
`concurrent use of ·aspirio ·with o_ther NSAID's shoUld. be
`avoi!l~d beeauae' this-m~y incr~ase' bleedili:g· or lead to' de-
`patients who have_ had ischemic 'stroke of transient isch~-
`fuia of the br;;;;,_· due to fibriil platelet emboli; (2) reduce the
`creased renhl fuiictiori~"·
`·
`· · ..
`risk of ~ascular JIIOrtality in patients with a suspected acute Orru· Hypoglycenrlcs: · 'Moderate doses~ of aspirio may m"
`crease j;Jie idfectiveness Of ural hYP~glY\:emic drugs, leading
`MI, (3) reduce the combined risk of death and nonfatal. MI
`fu pl;itients With a previous MI or unstable angina pectoris,
`tO hypoglyceiD.ia: .
`•· '·
`_,. · ·
`·
`ana:(4Jreducethe combined risk ofMI and sudden death in Uricosuric AgeiitS (Probenecid and 'SUlllnpyraztiD.ej: Saii-
`~~tients."!it):l. chronic stable ·angina pectoris.
`· " cylates antagonize the Uricosuric' actioii'ofiiricosuric agents.
`Revasc'Ilarization Procedures (Coronary Ar!ery Bypass
`Carcinogen~_sis, Mutagenesis,ll)lpaipnent of Fertility: Ad-
`Graft (CABG), Percutaneous Transluminal Coroilary.Angi-
`D:rinistr!ltiqn: of aspirill for'68 weeks at 0.5 p~rcent in the
`feiid of 'rats was not carcinogenic. tli. ·the Ames Salmonella
`O]Jl;>sty (PTGA), :ind Carotid End~rectomy): Aspirio_ i~ .in-
`IDeated in p~tients who have_ undeigone reVasculari.zation
`assay, S§pjrin was not mut~genic; ho"!ever, aspirin did in~
`procedures..(i:e., CABQ, PTCA,.~r carotid endarterectomy)
`duce chromosome .aberrations· in cultured human fibro-
`when_ther\i _is ·a.,preexisting ·condition for which aspirio js
`-)>lasts: Aspirio irlhi.bits ovulation iz> ra~. (See J;'re!:!la:ncy.)
`Fregn8IlcY: . Pregnant jyoiQ.en should JlnlY tljke .Sjijri)i_ if
`already.indicitted.
`· ·
`. ·
`·
`. .
`liheumatologic Disease Indications'(RbeumiJ.tOid Artliriti.s,
`clearly needed. Beeause of the kno\vn·effects·ofNSAlD's on
`Juvenile Rheumatoid Aitlni(is,'sp~ndyloli.rt!u'oiiathles; Os-
`the fetal cardiovascUlar system (closure of the ductus arte-
`riosus), use during _the third trimester,of pr.egnancy should
`teoarthritis, '!Jld the Artbrif!s arid Pleu