PDR®
`53
`1999
`
`EDITION
`
`PHYS CANS'
`DESK
`REFERENCE®
`
`Medical Consultant
`Ronald Arky, MD, Charles S. Davidson Professor of Medicine and Master, Francis Weld Peabody Society, Harvard Medical School
`
`Vice President of Directory Services: Stephen B. Greenberg
`
`Director of Product Management: David P. Reiss
`Senior Product M anager: Mark A. Friedman
`Associate Product Manager: Bill Shaughnessy
`Director of Sales: Dikran N. Barsamian
`National Sales Manager: Anthony Sorce
`National Account Manager: Don Bruccoleri
`Account Managers:
`Marion Gray, RPh
`.Lawrence C. Keary
`Jeffrey F. Pfohl
`Christopher N. Schmidt
`Stephen M. Silverberg
`Suzanne E. Yarrow, RN
`National Sales Manager, Trade Group: Bill Gaffney
`Director of Direct Marketing: Michael Bennett
`Direct Marketing Manager: Lorraine M. Loening
`Promotion Manager: Donna R. Lynn
`Director, Professional Support Services: Mukesh Mehta, RPh
`
`Senior Drug Information Specialist: Thomas Fleming, RPh
`Drug Information Specialist: Maria Deutsch , MS, RPh, CDE
`Editor, Special Projects: David W. Sifton
`Vice President of Production: David A. Pitier
`Director of Print Purchasing: Marjorie A. Duffy
`Director of Operations: Carrie Wi lliams
`M anager of Production: Kimberly H. Vivas
`Senior Production Coordinators: Amy B. Brooks, Dawn McCall
`Production Coordinator: Mary Ellen R. Breun
`PDR Data Manager: Jeffrey D. Schaefer
`Senior Format Editor: Gregory J. Westley
`Index Editors: Johanna M. Mazur, Robert N. Woerner
`Art Associate: Joan K. Akerlind
`Senior Digital Imaging Coordinator: Shawn W. Cahill
`Digital Imaging Coordinator: Frank J. McEl roy. Ill
`Electronic Publishing Designer: Robert K. Grossman
`Fulfillment Managers: Stephanie DeNardi. Kennet h Siebert
`
`I
`
`~ Copyright © 1999 and published by Medical Economics Company, Inc. at Montvale , NJ 07645-1 742. 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, record-
`ing, or otherwise) without the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE9
`, PD
`, PDR For Nonprescription Drugs• , PDR For
`Ophthalmologye, Pocket PDR", and The PDR" Family Guide to Prescription Drugs® are registered trademarks used herein under license. PDR Companion Guide™ ,
`PDR" for Herbal Medicines™, PDR" Medical Dictionary™ , PDR• Nurse's Handbookr"'. PDR® Nurse's Dictionaryr"' , The PDR" Family Guide Encyclopedia of Medical
`Carer"' , PDR"' Electronic Libraryr"'. and PDR" Drug Interactions, Side Effects, Indications, Contraindications Systemr"' are trademarks used herein under license.
`
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President. New Media: L. Suzanne BeDell; Vice President. Corporate
`Human Resources: Pamela M. Bilash : Vice President and Chief Information Officer: Steven M. Bressler; Senior Vice President, Anance. and Chief Anancial Officer: Thomas
`W. Ehardt; Vice President, Directory Services: Stephen B. Greenberg; Vice President, New Business Planning: Linda G. Hope; Executive Vice President. Healthcare Publishing
`and Communications: Thomas J. Kelly; Executive Vice President. Magazine Publishing: Lee A. Maniscalco; Vice President. Group Publisher: Terrence W. Meacock; Vice
`President, Production: David A. Pitier: Vice President, Group Publisher: Thomas C. Pizer; Vice President, Magazine Business Management: Eric Schlett: Senior Vice President,
`Operations: John R. Ware
`
`@ Printed on recycled paµer
`
`ISBN: 1-56363-288-8
`
`Purdue - IPR2018-00625; IPR2018-00717, Ex. 2021
`
`

`

`~ mcg/mL
`-Oral activated charcoal.
`>to.in a serum theophyllill,
`to insure that the .. ..._.
`
`00 mcg/mL
`, ral activated charcoal and
`
`,.
`
`obtain serial tbeophyllin,
`,ours to gauge tbe elf~
`ide further treatment de<i-
`
`moval if emesis, seimrel,o,
`ot be adequately controlW
`acorporeal Removal).
`ocg/mL
`iconvulsant therapy.
`oral activated chamJal 11111
`
`:30 mcg/mL (with mani_..
`I}
`of oral activated chan:oll
`obtain a serum theophyt]il,
`ll'li to insure that the .,.....
`
`n
`
`.t~btain serial theophylbll
`l hours to gauge the~
`guide further treatment
`
`i• ineffective for theophylline removal; ex(cid:173)
`ions in neonates have been minimally effec-
`
`or 600 mg Tablets can be taken once a day in
`II' evening. It is recommended that Uniphyl be
`. Patients should be advised that if they
`Uniphyl® with food it should be taken con(cid:173)
`rood apd if they take it in a fasted condition it
`y be taken fasted. It is important that the
`er dosed be dosed consistently with or with-
`
`ets are not to be chewed or crushed. The
`lllllY be split. Infrequently, patients receiving
`or 600 mg Tablets may pass an intact matrix
`atool or via colostomy. These matrix tablets
`little or no residual theophylline.
`ts, 12 years of age or older, who are taking
`release or controlled-release theophylline
`transferred to once-daily administration of
`mg Uniphyl® Tablets on a mg-for-mg basis.
`· zed that the peak and trough serum the(cid:173)
`produced by the once-daily dosing may vary
`uced by the previous product and/or regi-
`
`·ons: The steady-state peak serum the(cid:173)
`ation is a function of the dose, the dosing
`rate of theophylline absorption and clear(cid:173)
`. ual patient. Because of marked individ-
`in the rate of theophylline clearance, the
`achleve a peak serum theophylline concen-
`10-20 mcg/mL range varies fourfold among
`patients in the absence of factors known
`· e clearance (e.g., 400-1600 mg/day in
`old and 10-36 mg/kg/day in children 1- 9
`a given population there is no single theo(cid:173)
`t will provide both safe and effective serum
`fur all patients. Administration of the me-
`• dose required to achieve a therapeutic
`concentration in a given population may
`aub-therapeutic or potentially toxic serum
`ntrations in individual patients. For ex(cid:173)
`of 900 mg/d in adults < 60 years or 22 mg/
`1-9 years, the steady-state peak serum the(cid:173)
`tion will be < 10 mcg/mL in about 30% of
`mcg/mL in about 50% and 20-30 mcg/mL in
`·ents. The dose of theophylline must be
`11n the basis of eak serum theo h lline con-
`
`like adverse effects and excessive serum
`slow metabolizers can be avoided in most
`with a sufficiently low dose and slowly
`, if judged to be clinically indicated, in
`(See 'l;'able V). Dose increases should only
`ious dosage is well tolerated and at in(cid:173)
`than 3 days to allow serum theophylline
`lo reach tbe new steady-state. Dosage ad(cid:173)
`he guided by serum theophylline concen(cid:173)
`ent (see PRECAUTIONS, Laboratory
`GE AND ADMINISTRATION, Tahle VI).
`· rs should instruct patients and care giv(cid:173)
`any dosage that causes adverse effects, to
`'cation until these symptoms are gone and
`therapy at a lower, previously tolerated dos(cid:173)
`GS).
`'Ymptoms are well controlled, there are no
`effects, and no intervening factors that
`age requirements (see WARNINGS a nd
`), serum
`theophylline concentrations
`at 6 month intervals for rapidly grow(cid:173)
`at yearly intervals for all others. In acutely
`theophylline concentrations should be
`uent intervals, e.g., every 24 hours.
`'butes poorly into body fat. therefore.
`he calculated on the basis of ideal body
`
`·
`
`t.heophylline dosing titration schema rec(cid:173)
`Patients in various age groups and cHnical
`Table VI contains recommendations for the(cid:173)
`. adjustment based upon serum theophyl(cid:173)
`ons. Application of these general dosing
`to individual atients must take into ac(cid:173)
`clinical characteristics of each atient . In
`mmendations should serve as t he u
`er
`lcfustments in order to decrease the risk
`~ us adverse events associated with un(cid:173)
`eases in serum theo h lfine concentra-
`
`Table V. Dosing initiation and titration
`(as anhydrous theophylline). •
`A. Children (1 2-1 5 years) and adults (1 !Hro years)
`without risk factors for impaired clearance.
`Children > 45 kg
`and adults
`
`Children < 45 kg
`
`Titration Step
`
`1. Starting
`Dosage
`
`2. After 3 days,
`if tolerated,
`increase dose to:
`3. After 3 more
`days, if tolerated
`and if needed
`increase dose to:
`
`12-14 mg/kg/day
`up to a maximum
`of 300 mg/day
`admin. QD*
`16 mg/kg/day up to
`a maximum of 400
`mg/day admin. QD*
`20 mg/kg/day up to
`a maximum of 600
`mg/day admin. QD*
`
`300-400 mg/dayt
`admin. QD*
`
`400-600 mg/dayt
`admin. QD*
`
`As with all theo(cid:173)
`phylline products,
`doses greater than
`600 mg should be
`titrated according
`to blood level
`(See Table VI)
`
`tlf caffeine-like adverse effects occur, then consideration
`should be given to a lower dose and titrating the dose more
`slowly (see ADVERSE REACTIONS).
`
`B. Patients With Risk Factors For Impaired Clearance, The
`Elderly (>60 Years), And Those In Whom It Is Not Feasible
`To Monitor Serum Theophylline Concentrations:
`In children 12-15 years of age, the theophylline dose should
`not exceed 16 mg/kg/day up to a maximum of 400 mg/day in
`the presence of risk factors for reduced theophylline clear(cid:173)
`ance (see WARNINGS) or if it is not feasible to monitor
`serum theophylline concentrations.
`In adolescents ;a:16 years and adults, including the elderly,
`the theophylline dose should not exceed 400 mg/day in the
`presence of risk factors for reduced theophylline clearance
`(see WARNINGS) or if it is not feasible to monitor serum
`theophylline concentrations.
`*Patients with more rapid metabolism clinically identified
`by higher than average dose requirements, should receive a
`smaller dose more frequently (every 12 hours) to prevent
`breakthrough symptoms resulting from low trough concen(cid:173)
`trations before the next dose.
`
`Table VI. Dosage adjustment guided by serum
`theophylline concentration.
`Peak Serum
`Concentration
`
`Dosage Adjustment
`
`< 9.9 mcg/mL
`
`10-14.9 mcg/mL
`
`15-19.9 mcg/mL
`
`20-24.9 mcg/mL
`
`25-30 mcg/mL
`
`>30 mcg/mL
`
`If symptoms are not controlled and
`current dosage is tolerated, increase
`dose about 25%. Recheck serum
`concentration after three days for
`further dosage adjustment.
`If symptoms are controlled and
`current dosage is tolerated,
`maintain dose and recheck serum
`concentration at 6-12 month
`intervals. 'I
`If symptoms are not controlled and
`current dosage is tolerated consider
`adding additional medication(s) to
`treatment regimen.
`Consider 10% decrease in dose to
`provide greater margin of safety
`even if current dosage is tolerated. 'i
`Decrease dose by 25% even if no
`adverse effects are present. Recheck
`serum concentration after 3 days to
`guide further dosage_adjustment.
`Skip next dose and decrease
`subsequent doses at least 25'J( even
`if no adverse effects are present.
`Recheck serum concentration after 3
`days to guide further dosage
`adjustment. If symptomatic,
`consider whether overdose
`treatment is indicated (see
`recommendations for chronic
`overdosage).
`Treat overdose as indicated (see
`recommendations for chronic
`overdosage). If tbeophylline is
`subsequently resumed, decrease
`dose by at least 50'it and recheck
`serum concentration after 3 days to
`guide further dosage adjustment.
`
`'I Dose reduction and/or serum theophylline concentration
`measurement is indicated whenever adverse effects are pre·
`sent, physiologic abnormalities that can reduce tbeophylline
`clearance occur (e.g., sustained fever). or a drug th at inter(cid:173)
`acts with theoph yl Hne is added or discontinued (see WARN(cid:173)
`INGS).
`
`PURDUE PHARMN2569
`
`HOW SUPPLIED
`Uniphyl® (theophylline, anhydrous) 400 mg Controlled(cid:173)
`Release Tablets are supplied in white-opaque plastic bottles
`containing 100 tablets (NDC 0034-7004-80) or 500 tablets
`(NDC 0034-7004-70).
`Each round, white, scored 400 mg tablet bears the symbol
`PF on one side and is marked U400 on the other side .
`Uniphyl® (theophylHne, anhydrous) 600 mg Controlled(cid:173)
`Release Tablets are supplied in white-opaque plastic bottles
`containing 100 tablets (NDC 0034-7006-80).
`Each rectangular, concave, white 600 mg scored tablet bears
`the symbol PF on one side and is marked U600 on the other
`side.
`Store at controlled room temperature 15°-30°C (59°-86°F).
`Dispense in tight, light-resistant container.
`CAUTION: Federal law prohibits dispensing without pre(cid:173)
`scription.
`The Purdue Frederick Company
`Norwalk, CT 06850-3590
`Copyright ©1996 The Purdue Frederick Company
`U.S. Patent Numbers 4,235,870 and 4,366,310
`June 12, 1996
`Rl374
`Shown in Product Identification Guide, page 333
`
`EDUCATIONAL MATERIAL
`
`Laxative Protocol Sheets (PS77) 1 page (pad of 25)
`Available to physicians, nurses and pharmacists
`
`Purdue Pharma L.P_
`100 CONNECTICUT AVENUE
`NORWALK, CT 06850-3590
`
`DHCplus® Capsules
`
`MS Contin® Tablets-see listing under The Purdue Freder(cid:173)
`ick Company, page 2556
`
`MSIR® Capsules-1lee listing under The Purdue Frederick
`Company, page 2559
`
`MSIR® Tablets-see listing under The Purdue Frederick
`Company, page 2559
`
`MSrn® Liquid-see listing under The Purdue Frederick
`Company, page 2559
`
`@: ~
`OXYCONTIN®
`(OXVCODONE HCL CONTROLLED-RELEASE) TABLETS
`Warning-May be habit forming.
`10mg 20mg 40mg 80mg•
`
`•so mg For use in opioid tolerant patients only.
`
`DESCRIPTION
`Oi,.-yContin® (oxycodone hydrochloride controlled-release)
`tablets are an opioid analgesic supplied in 10 mg, 20 mg, 40
`mg, and 80 mg tablet strengths for oral administration. The
`tablet strengths describe the amount of oxycodone per tab(cid:173)
`let as the hydrochloride salt. The structural form ula for oxy(cid:173)
`codone hydrochloride is as follows :
`
`H: ,CO~
`
`,..r.,,,,
`o·
`
`OH H•C/
`N,
`
`CH3
`
`0
`
`MW 351.83
`C18H 21NO, • HC1
`The chemical formula is 4, 5-epoxy-14-hydroxy-3-methoxy-
`17-methylmorphinan-6-one hydrochloride.
`Oxycodone is a whitR, odorless crystalline powder derived
`from the opium alkaloid, thebaine. Oxycodone hydrochlo(cid:173)
`ride di ssolves in water (1 g in 6 to 7 mL). It. is slightly sol(cid:173)
`uble in alcohol (octanol water partition coefficient 0.7). The
`tablets contain the following inactive ingredients: ammonio
`
`Consult 1 9 9 9 POR.t supplements and future editions for revisions
`
`Continued on next page
`
`Purdue - IPR2018-00625; IPR2018-00717, Ex. 2021
`
`

`

`of OxyContin to immediate-release oral dosage fo rms is
`100%. Upon repeated dosing in normal volunteers, steady(cid:173)
`state levels were achieved within 24-36 hours. Dose propor(cid:173)
`tionality has been established for the 10 mg, 20 mg, 40 mg,
`and 80 mg tablet strengths for both peak plasma levels
`(Cm,.) and extent of absorption (AUC). Oxycodone is exten(cid:173)
`sively metabolized and eliminated primarily in the urine as
`both conjugated and unconjugated metabolites. The appar(cid:173)
`ent elimination half-life of oxycodone following the admin(cid:173)
`istration of OxyContin was 4.5 hours compared to 3.2 hours
`for immediate-release oxycodone.
`Abso1ption
`About 60% to 87% of an oral dose of oxycodone reaches the
`central compartment in comparison to a parenteral dose.
`This high oral bioavailability is due to low pre-systemic
`and/or first-pass metabolism. In normal volunteers the t 1/ 2
`of absorption is 0.4 hour s for immediate-release oral
`oxycodone. In contrast, OxyContin tablets exhibit a biphasic
`absorption pattern with two apparent absorption half-times
`of 0.6 and 6.9 hours, wh.ich describes the initial release of
`oxycodone from the tablet followed by a prolonged release.
`
`PlasinaOryeadoneByTim,
`
`] 100-r--o=o:;;::c;:;,:;:~~~~~~~~--i
`!
`i
`~ 10 1
`i I-'-~~~~~~-,-~~~~-,-~-,-~->
`
`w n ~
`
`o
`
`Hou, From Dos:ng
`_._ ,omg -+20mg ..... 40mg -0-SOmgSJngleOoee
`-K- ,a mg q12h Steady-mat,
`
`Dose proportionality has been established for the 10 mg, 20
`mg, 40 mg, and 80 mg tablet st rengths for both peak plasma
`concentrations (Cm.,) and extent of absorption (AUC) (see
`Table 1 below). Given the short half-life of elimination of
`oxycodone from OxyContin, steady-state plasma concentra(cid:173)
`tions of oxycodone are achieved with.in 24-36 hours of initi(cid:173)
`ation of dosing with OxyContin tablets. In a study compar(cid:173)
`ing 10 mg of OxyContin every 12 hours to 5 mg of immedi(cid:173)
`ate-release oxycodone every 6 hours the two treatments
`were found to be equivalent for AUC and Cm,,., and similar
`for Cmin (trough) concentrations. There was less fluctuation
`in plasma concentrations for the OxyContin tablets than for
`the immediate-release formul ation.
`[See table 1 below]
`Food Effects
`In contrast to immediate-release formulations, food has no
`significant effect on the a bsorption of oxycodone from
`OxyContin. Oxycodone release from OxyContin tablets is
`pH independent.
`Distribution
`Following intravenous administration, the volume of distri(cid:173)
`bution (Vss) for oxycodone was 2.6Ukg. Oxycodone binding
`to plasma protein at 37°C and a pH of 7.4 was about 45%.
`Once absorbed, oxycodone is distributed to skeletal muscle,
`liver, intestinal tract, lungs, spleen and brain. Oxycodone
`has been found in breast milk (see PRECAUTIONS).
`Metabolism
`Oxycodone hydrochlor ide is extensively metabolized to
`noroxycodone, oxymorphone, and their glucuronides. The
`major circulating metabolite is noroxycodone with an AUC
`ratio of 0.6 relative to t hat of o:,,.'Ycodone. Noroxycodone is
`reported to be a considerably weaker analgesic than
`
`.
`oxycodone. Oxymorphone, although
`tivity, is present in the plasma o n !~
`The correlation between oxymorphone
`opioid effects was much less than that ~
`plasma concentrations. The analgesiaee.i~,
`other metabolites is not known at p r~~ ...... ~
`The formation of oxymorphone, but not
`•
`mediated by CYP2D6 and as such its ~ ~
`ory, be _affected by other drugs (see Dru~~
`Excretion
`-·"I
`Oxycodone and its metabolites are ex~
`the kidney. The amounts measured in the
`.~
`reported as follows: free oxycodone up t.o ;:: ti.;
`oxycodone up to 50%; free oxymorphone 0%· ~
`ymorphone s 14%; both free and conj ·~
`have been found in the urine but no t~~
`IIIL 'l\t-;:::
`plasma clearance was 0.8 Umin for adu!ta
`·
`Special Populations
`Tbe plasma concentrations of oxycodone are..__ _
`Elderly
`young subjects. There were no differences DI .:;::aw
`affected by age, being 15% greater in elderly•~
`
`reporting between young and elderly subjec:ta,
`Gender
`Female subjects have, on average, plasma ~
`centrations up to 25% h.igher than males oa a~
`adjusted basis. The reason for th.is difference ii_....
`.__
`Renal Impairment
`Preliminary data from a study involving P8tienta Willl
`to sever e renal dysfunction (creatinine clears..,.•
`min) show peak plasma oxycodone and ~ 1111
`centrations 50% and 20% higher, respectively lllll'AUC Ila.
`ues for oxycodone, noroxycodone and ~ -
`50% and 40% higher than normal subjecta, - . .
`This is accompanied by an increase in eedlltioa ._-,
`differences in respiratory rate, pupillary ~
`several other measures of drug effect. There -la·
`It
`in t 1
`CAUTIONS).
`Hepatic Impairment
`Preliminary data from a study involving patientnilli-'!
`to moderate hepatic dysfundion show peat - (cid:173)
`
`higher, respectively, than normal subjects. AUC . , . . .
`
`/ 2 of elimination for oxycodone of only 1 hour(.::
`oxycodone and noroxycodone concentrationa 50'l llli! *
`95% and 65% higher, respectively. Oxymorplua "*
`plasma concentrations and AUC values are lower.,_
`and 40%. These differences are accompanied byinenast,
`some, but not other, drug effects. The t112 l!!imiulia•
`oxycodone increased by 2.3 hours (see PRECAUTKJllll.=i
`Rectal Administration
`Rectal administration of OxyContin tablets ia 1111$ -
`mended. Preliminary data from a study involvinglhalt
`volunteers, show OxyContin tablets administienll PII'•
`tum resulted in an AUC 39% greater and a c_ 91 lliallr
`than tablets administered by mouth (seeJ'RECAD'll».
`Drug-Drug Interactions (see PRECAUTIONS)
`Oxycodone is metabolized in part via CYP2D6 111..,_
`phone wh.ich represents less than 15% of the tolallllllilit
`tered dose. Th.is route of elimination can be blo!W1i'I
`variety of drugs (e.g., certain cardiovascular drop 11111 . .
`depressants). Patients receiving such drugs conaadlit
`with OxyContin do not appear ta present di1linai M
`peutic profiles than other patients.
`CLINICAL TRIALS
`OxyContin® (oxycodone hydrochloride con~
`tablets were evaluated in studies involving 713 ....
`with either cancer or non-cancer pain. All patianll reaiMlt
`OxyContin were dosed q12h. Efficacy comparable ti~
`forms of oral oxycodone was demonstrated in clinillll.,..
`
`ies using pharmacokinetic, pharmacodynamic and..,
`
`outcomes. The outcome of these trials indicat.ed: (U ,.(cid:173)
`tive relationship between dose and plasma oxymclla•
`centration, (2) a positive relations hip between ~llf'
`
`2570/PURDUE PHARMA
`OxyContin-Cont.
`
`methacrylate copolymer, hydroxypropyl methylcellulose,
`lactose, magnesium stearate, povidone, red iron oxide (20
`mg strength tablet only), stearyl alcohol, talc, titanium di(cid:173)
`oxide, triacetin, yellow iron oxide (40 mg strength tablet
`only), yellow iron oxide with FD&C blue No. 2 (80 mg
`strength tablet only), and other ingredients.
`OxyContin~ 80 mg Tablets ARE FOR USE IN OPIOID TOL(cid:173)
`ERANT PATIENTS ONLY.
`CLINICAL PHARMACOLOGY
`Central Nervous System
`Oxycodone is a pure agonist opioid whose principal thera(cid:173)
`peutic action is analgesia. Other therapeutic effects of oxy(cid:173)
`codone include anxiolysis, euphoria and feeli ngs of relax(cid:173)
`ation. Like all pure opioid agonists, there is no ceiling effect
`to analgesia, such as is seen with partial agonists or non(cid:173)
`opioid analgesics.
`The precise mechanism of the analges ic action is unknown.
`However, specific CNS opioid receptors fo r endogenous com(cid:173)
`pounds with opioid-like activity have been identified
`throughout the brain and spinal cord and play a role in the
`analgesic effects of this drug.
`Oxycodone produces respiratory depression by direct action
`on brain stem respiratory centers. The respiratory depres(cid:173)
`sion involves both a reduction in the responsiveness of the
`brain stem respiratory centers to increases in carbon diox(cid:173)
`ide tension and to electrical stimulation.
`Oxycodone depresses the cough reflex by direct effect on the
`cough center in the medulla. Antitussive effects may occur
`with doses lower than those usually required for analgesia.
`Oxycodone causes miosis, even in total darkness. Pinpoint
`pupils are a sign of opioid overdose but are not pathogno(cid:173)
`monic. Marked mydriasis rather than miosis may be seen
`due to hypoxia in overdose situations.
`Gastrointestinal Tract and Other Smooth Muscle
`Oxycodone causes a reduction in motility associated with an
`increase in smooth muscle tone in the antrum of the stom(cid:173)
`ach and duodenum. Digestion of food in the small intestine
`is delayed and propulsive contractions are decreased. Pro(cid:173)
`pulsive peristaltic waves in the colon are decreased, while
`tone may be increased to the point of spa m resulting in
`constipation. Other opioid-induced effects may include a re(cid:173)
`duction in gastric, biliary and pancreatic secretions, spasm
`of sphincter of Oddi, and transient elevations in serum am(cid:173)
`ylase.
`Cardiovascular System
`Oxycodone may produce release of histamine with or with(cid:173)
`out associated peripheral vasodilation. Manifestations of
`histamine release and/or peripheral vasodilation may in(cid:173)
`clude pruritus, flushing, red eyes, sweating, and/or ortho(cid:173)
`static hypotension .
`Concentration-Efficacy Relationships (Pharmacodynam(cid:173)
`ics)
`Studies in normal volunteers and patients reveal predict(cid:173)
`able relationships between oxycodone dosage and plasma
`oxycodone concentrations, as well as between concentration
`and certain expected opioid effects. In normal volunteers
`these include pupillary constriction, sedation and overall
`"drug effect" and in patients, analgesia and feelings of "re(cid:173)
`laxation." In non-tolerant patients, analgesia is not usually
`seen at a plasma oxycodone concentr ation of less than 5-10
`ng/mL.
`As with all opioids, the minimum effective plasma concen(cid:173)
`tration for analgesia will vary widely among patients, espe(cid:173)
`cially a mong patients who have been previously treated
`with potent agonist opioids. As a result, patients need to be
`treated with individualized titration of dosage to the desired
`effect. The minimum effective analgesic concentration of
`oxycodone for any individual patient may increase with re(cid:173)
`peated dosing due to an increase in pain and/or the devel(cid:173)
`opment of tolerance.
`Concentration-Adverse Experience Relationships
`OxyContin tablets are associated with typical opioid-related
`adverse experiences similar to those seen with immediate(cid:173)
`release oxycodone and all opioids. There is a general rela(cid:173)
`tionship between increasing oxycodone plasma concentra(cid:173)
`tion and increasing frequency of dose-related opioid adverse
`experiences such as nausea, vomiting, CNS effects and res(cid:173)
`piratory depression. In opioid-tolerant patients, the situa(cid:173)
`tion is altered by the development of tolerance to opioid(cid:173)
`related side effects, and the relationship is poorly under(cid:173)
`stood.
`As with all opioids, the dose must be individualized (see
`DOSAGE AND ADMINISTRATION), because the effective
`analgesic dose for some patients will be too h.igh to be toler(cid:173)
`ated by other patients.
`PHARMACOKINETICS AND METABOLISM
`The activity of OxyContin® (oxycodone hydrochloride con(cid:173)
`trolled-release) tablets is primarily due to the parent drug
`oxycodone. OxyContin tablets are designed to provide con(cid:173)
`trolled delivery of oxycodone over 12 hours. Oxycodone is
`well absorbed from OxyContin tablets with an oral bioavail(cid:173)
`ability of from 60% to 87%. The relative oral bioavailability
`
`Table 1
`Mean [% coefficient variation}
`Regimen/Dosage Form
`
`Single Dose
`10 mg OxyContin
`
`20 mg OxyContin
`
`40 mg OxyContin
`
`AUC
`( ng· hr/mL)t
`
`100. 7 (26.6]
`
`207.5 (35.9]
`
`423. 1 [33.3]
`
`80 mg OxyContin*
`
`1085.5 [32.3]
`
`cmax
`(ng/mL)
`
`10.6 [20.1]
`
`21.4 (36.6]
`
`39.3 [34.0]
`
`98.5 (32.1]
`
`T max
`(hrs)
`
`2.7 [44.1]
`
`3.2 (57.9]
`
`3.1 [77.4]
`
`2.1 (52.3]
`
`Multiple Dose
`10 mg OxyContin
`Tablets q 12h
`
`103.6 [38.6]
`
`15.1 (31.0]
`
`3.2 [69.5]
`
`TroughC-.
`(ngfmLI-
`
`n.a.
`
`-
`n.a. -
`n.a. --
`n.a. ---
`
`7 . 2~
`
`5 mg·immediate-
`99.0 (36.2]
`15.5 [28.8]
`release q6h
`t for single-dose AUC=AUC0_,0 , ; for multiple-dose AUC=AUC0-T
`• data obtained while volunteers received naltexone wh.ich can enhance absorption.
`
`1.6 [49.7]
`
`7 . 4~
`
`Information will be superseded by supplements and subsequent editions
`
`Purdue - IPR2018-00625; IPR2018-00717, Ex. 2021
`
`

`

`pRODUCT INFORMATION
`
`,,;,,i,.e concentration and analgesia, and (3) an observed
`-k to trou_gh variation in plasma concentr~tion with
`:;;contin lymg within the observed range established with
`fidoling of immediate-release oxycodone in clinical popu(cid:173)
`Jllillll at the same total daily dose.
`111 dJnical trials, OxyContin tablets w~re substituted for a
`wide variety of a nalgesics, mcludmg acetammophen
`!APAP), aspirin (ASA), other non-steroidal anti-inflamma(cid:173)
`ta11drugs (NSAIDs), opioid combination products and sin(cid:173)
`p-40tity opioids, primarily morphine. In cancer patients
`.-wig adequate opioid therapy at baseline, pain inten(cid:173)
`lily 1CQres and acceptability of therapy remained un(cid:173)
`diin,ed by transfer to OxyContin. For non-cancer pain pa(cid:173)
`tillltl who had moderate to severe pain at baseline on pm
`opioid therapy, pain control and acceptability of therapy im(cid:173)
`~ with the introduction of fixed-interval therapy with
`~tin.
`U• in Cancer Pain
`()lyContin was studied in three double-blind, controlled
`cfiDical trials involving 341 cancer patients and several
`~-label trials with therapy durations of over 10 months.
`Ttlo. double-blind, controlled clinical studies indicated that
`()lyContin dosed ql2h produced analgesic efficacy equiva(cid:173)
`Imt to immediate-release oxycodone dosed qid at the same
`u,taJ daily dose. Peak and trough plasma concentr ations at(cid:173)
`tained were similar to those attained with immediate-re(cid:173)
`p oxycodone at equivalent total daily doses. With titra(cid:173)
`tion to analgesic effect and proper use of rescue medication,
`nearly every patient achieved adequate pain control with
`~ntin.
`ID lbe third study, a double-blind, active-controlled, cross(cid:173)
`om trial, OxyContin dosed ql2h was shown to be equiva(cid:173)
`lent in efficacy and safety to immediate-release oxycodone
`doled qid at the same total daily dose. Patients were able to
`be titrated to an acceptable analgesic effect with either
`OlyContin or immediate-release oxycodone with both treat(cid:173)
`ments providing stable pain control within 2 days in most
`pltients.
`ID patients with cancer pain, the total daily OxyContin
`m tested ranged from 20 mg to 640 mg per day. The av(cid:173)
`fflll' total daily dose was approximately 105 mg per day.
`Slluliu in Non-Cancer Pain
`A double-blind, placebo-controlled, fixed-dose, parallel
`group study was conducted in 133 patients with moderate to
`se,ere osteoarthritis pain, who were judged as having inad(cid:173)
`equate pain control with prn opioids and maximal non(cid:173)
`steroid:tl anti-inflammatory therapy. In this study, 20 mg
`Ozyeontin ql2h significantly decreased pain and improved
`quality of life, mood and sleep, relative to placebo. Both
`doee-ooncentration and concentration-effect relationships
`were noted with a minimum effective plasma oxycodone
`COl!a!ntration of approximately 5-10 ng/mL.
`In a double-blind, active-controlled, crossover study involv(cid:173)
`~ 57 patients with low-back pain inadequately controlled
`rib pm opioids and non-opioid therapy, OxyContin admin-
`181ered ql2h provided analgesia equivalent to immed iate(cid:173)
`rolease oxycodone administered qid. Patients could be ti(cid:173)
`trated to an acceptable analgesic effect with either
`()qeootin or immediate-release forms of oxycodone.
`Suigk-Dose Comparison with Standard Therapy
`A SJDgle-dose, double-blind, placebo-controlled, post-opera(cid:173)
`: . study of 182 patients was conducted utilizing graded
`ofOxyContin (10, 20 and 30 mg). Twenty and 30 mg of
`Oqcontin gave equivalent peak analgesic effect compared
`
`= hro oxycodone 5 mg /acetaminophen 325 mg tablets and
`
`~5 mg lillmediate-release oxycodone, wh ile the 10 mg
`of Oxyeontin was intermediate between both the im(cid:173)
`illediate-release and combination products and placebo. The
`: :.or analgesic action with OxyContin occurred within 1
`m most patients following oral administration.
`~~-tin is not recommended pre-operatively (preemptive
`_.,.,a) or for the management of pain in the immediate
`IIO!t-operative period (the first 12 to 24 hours following sur(cid:173)
`:;) because the safety or appropriateness of fixed-dose,
`~acti~g- opioids in this setting has not been established.
`r Clinical Trials
`~"Pen-label trials involving approximately 200 patients
`the cancer-related and non-cancer pain, dosed according to
`~kage msert recommendations, appropriate analgesic
`. •eness was noted without regard to age, gender, race,
`obte disease state. There were no unusual drug interactions
`~ed_m patients receiving a wide range of medications
`?o,
`~ _m these populations.
`~01d-naive patients, the average total daily dose of
`~ tin was approximately 40 mg per day. There was no
`lllon of oxycodone and metabolite accumulation during
`%ii dths of therapy. For cancer pain patients the average
`!her,; aily dose was 105 mg (range 20 to 720 mg) per day.
`~ Was a s1gruficant decrease in acute opioid-related side
`"etks • except for constipation, during the first several
`illliJ ~f therapy. Development of significant tolerance to
`A ies,a was uncommon.
`
`Ilg~: of patients have been treated with OxyContin 80
`
`llfety lets. There were no differences in the effica cy or
`Profiles than seen with the other tablet strengths.
`
`INDICATIONS AND USAGE
`OxyContin® tablets are a controlled-release oral formula(cid:173)
`tion of oxycodone hydrochloride indicated for the manage(cid:173)
`ment of moderate to severe pain where use of an opioid an(cid:173)
`algesic is appropriate for more than a few days. (See: CLIN(cid:173)
`ICAL PHARMACOLOGY; CLINICAL TRIALS).
`CONTRAINDICATIONS
`OxyContin® is contraindicated in patients with known hy(cid:173)
`persensitivity to oxycodone, or in any situation where
`opioids are contraindicated. This includes patients with sig(cid:173)
`nificant respiratory depression (in unmonitored settings or
`the absence