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`EXHIBIT
`
`MYLAN PHARMS. INC. EXHIBIT 1088 PAGE 1
`
`

`

`5**"
`
`The Official
`
`Home of
`
`i Physicians' desk roTerePce.
`i ckJ. C4 (20001
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`health
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`When you need healthcare information visit the one site that
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`MYLAN PHARMS. INC. EXHIBIT 1088 PAGE 2
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`

`

`.y
`
`PDR'
`
`EDITION
`
`2000
`
`D
`
`Senior Vice President, Directory Services: Paul Walsh
`Director of Product Management: Mark A. Friedman
`Associate Product Manager: Bill Shaughnessy
`Senior Business Manager: Mark S. Ritchin
`Rnanclal Analyst; Wayne M. SoUis
`Director of Sales: Dikran N. Barsamian
`N«ional Sales Manager, Pharmaceutical Sales: Anthony Sorce
`National Account Manager; Don Bruccoleri
`Senior Account Manager: Frank Karkowsky
`Account Managers:
`Marion Gray, RPh
`Lawrence C. Keary
`Jeffrey F. Pfohl
`Suzanne E. Yarrow, RN
`Electronic Sales Account Manager: Stephen M, Silverberg
`National Sales Maru^r, Medical Economics Trade Sales: Bill Gaffney
`Director of Direct Marketing: Michael Bennett
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`Senior Marketing Analyst: Dina A. Maeder
`
`Director, New Business Development and
`Professional Support Services: Mukesh Mehta, RPh
`Manager, Drug Information Services: Thomas Reming, RPh
`Drug Infonnatlon Specialist: Maria Deutsch, MS, RPh, CDE
`Editor, Directory Services: David W, Sifton
`Senior Associate Editor: Lori Murray
`Director of Production: Carrie Williams
`Manager of Production: Kimberly H. Vivas
`Senior Production Coordinator: Amy B. Brooks
`Production Coordinators: Gianna Caradonna, Maria Volpati
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`
`published by Medical Economics Company, Inc. at Montvale, NJ 07645-1742. All rights resen/ed. None of the content of this publication may
`otherwise) w4h&?****' 'o a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or
`Guide to Presc^i^POnnission of the publisher. PHYSICIANS' DESK REFERENCE*. PDR*, PDR For Ophthalmology*, Pocket PDR*, and The PDR' Family
`PDR* lor Herbal
`'09'Slered trademarks used herein under license, PDR For Nonprescriplion Drugs and Dietary Supplements’", PDR Companion Guide™,
`Caro™ The PDR* Fa't
`Medical Dictionary™, PDR* Nurse's Drug Handbook™, PDR* Nurse's Dictionary™. The PDR* Family Guide Encyclopedia of Medical
`Counlo'r Drugs™ and
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`Fesoumes’^ameh
`Gray Vico President New nusine^°Infonmtion Officer: Steven M. Dressier; Chief Financial Officer: Christopher Caridi; Vice President and Controller: Barry
`^ireeforv Sendee,:- Pe,.( wuch •
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`I , ror Vice President, Operations: John R. Ware; Senior Vice President, Internet Stralesies: Raymond Zoellet
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`© Printed on recycled paper
`
`ISBN: 1.56363-330-2
`
`MYLAN PHARMS. INC. EXHIBIT 1088 PAGE 3
`
`

`

`CONTENTS
`
`Manufacturers’ Index (White Pages)
`Section 1
`Lists all pharmaceutical manufacturers participating in PHYSICIANS' DESK REFERENCE.
`Includes addresses, phone numbers, and emergency contacts. Shows each manufacturer's
`products and.the page number of those described in PDR.
`Brand and Generic Name Index (Pink Pages)
`Section 2.
`Gives the page number of each product by brand and generic name.
`Product Category Index (Blue Pages) _________ 201
`Section 3
`Lists all fully described products by prescribing category. An overview of the headings
`appears on pages 201 and 202.
`Product Identification Guide (Gray Pages)
`Section 4
`Presents full-color, actual-size photos of tablets and capsules, plus pictures of a variety of other
`dosage forms and packages. Arranged alphabetically by manufacturer.
`Product Information (White Pages)
`
`1
`
`101
`
`301
`
`401
`
`Section 5
`The main section of the book. Includes entries for over 3,200 pharmaceuticals. Listings are
`arranged alphabetically by manufacturer.
`Diagnostic Product Information 3348
`
`Section 6
`Gives usage guidelines for a variety of common diagnostic agents. Arranged alphabetically by manufacturer.
`
`Key to Contoiied Substances Categories......................... .....................................................................................345
`Gives the definition of each category and the prescribing limitiaiions that apply.
`Key to FDA Use-in-Pregnancy Ratings.................................................................................................................... 345
`Provides the exact interpretation of each risk/benefit rating.
`U.S. Food and Drug Administration Telephone Directory...................................................................................... 346
`Gives numbers of key reporting programs and information services.
`Common Laboratory Test Values........................................ .....................................................................................347
`Generally accepted normal values for a selection of common laboratory assays on serum, plasma, and blood.
`Poison Control Centers................................. ..................... ..................................... ..............................................3357
`A national directory arranged alphabetically by state and city. ,
`Adverse Event Report Forms..................................................................................................................................3361
`Contains master copies and instructions for completion.
`
`MYLAN PHARMS. INC. EXHIBIT 1088 PAGE 4
`
`

`

`./
`
`PRODUCT INFORMATION
`Tel-E‘Dosc
`Dose
`Bottle
`Shape
`NDC 0004-0262-49.
`NDC 0004-0262-01
`5 mg
`oval
`NDC 0004-0263-49
`NDC 0004-0263-01
`10 mg
`oval
`NDC 0004-0264-49
`NDC 0004-0264-01
`20 mg
`oval
`NDC 0004-0265-49
`NDC 0004-0265-01
`capsule-shaped
`100 mg
`mg, 10 mg, 20 mg, or 100 mg, respectively). On the opposite
`Angioedcma has been reported in a patient exposed to
`aide, the tablet is debossed with 5,10,20, or 100 to indicate
`DENIADEX who was later found to be allergic to suUa
`the dose.
`Of the adverse reactions during placebo-controlled trials
`DEMADEX for intravenous injection is supplied in clear
`listed without taking into account assessment of related­
`ampuls containing 2 mL {20 mg, NDC 0004-0267-06) or 5
`ness to drug therapy, arthritis and various other nonspecific
`mL (50 mg. NDC 0004-0268-06) of a 10 m^mL sterile solu-
`musculoskeletal problems were more frequently reported in
`association with DEMADEX than with placebo, even
`Storage: Store all dosage forms at 15* to 30*C (59* to 86“F).
`though gout was somewhat more frequently associated with
`Do not freeze.
`placebo These reactions did not increase in frequency or se­
`verity with the dose of DEMADEX. One patient in the group
`•Tel-E-Dose is a registered trademark of Hoffmann-La
`treated with DEMADEX withdrew due to myalgia, and one
`Roche Inc.
`in the placebo group withdrew due to gout.
`Tablets manufactured by:
`Hypokalemia: See WARNINGS.
`Bochringer Mannheim, GmbH, Mannheim, Germany
`Ampuls manufactured by:
`OVERDOSAGE
`There is no human experience with overdoses of
`Abbott Laboratories, North Chicago, IL 600C4
`DEMADEX but the signs and symptoms of overdosage can
`Revised: April 1998
`be anticipated to be those of excessive pharmacologic effect,
`Shou;n in Product Jdcnti/icQtion Guide, page 334
`dehydration hypovolemia, hypotension, hyponatremia, hy
`pokalemia, hypochloremic alkalosis and hemoconcentra-
`tion. Treatment of overdosage should consist of fluid and
`uSirato^ drieSaflons of serum levels of torsemide and
`iU metabolites arc not widely available.
`No data are available to suggest physiological jnoneuyere
`(eg, maneuvers to change the pit of the unne) that might
`areelerate elimination of torsem.de and its rnetabolites.
`Torsemide is not dialyzable. so hemodialysis will not accel-
`erate elimination.
`DOSAGE AND administration
`,
`.
`General- DEMADEX tablets may be given at any time in
`relation to a meal, as convenient. Spcaal dosage adjustment
`5 S“S«W .lOElUUtt ml ■«!
`
`ROCHE LABORATORIES/2631
`elimination half-life of naproxen is unchanged across prod-
`ucU ranging from 12 to 17 hours. Steady-state levels of
`naproxen are reached in 4 to 5 days, and the degree of
`naproxen accumulation is consistent with this half-life. This
`suggests that the differences in pattern of release play only
`a negligible role in the attainment of steady-state plasma
`levels.
`Absorprion;
`Immediate Release: After administration of NAPROSYN
`tablets, peak plasma levels are attained in 2 to 4 hours. Af­
`ter oral administration of ANAPROX, peak plasma levels
`are attained in 1 to 2 hours. The difference in rates between
`the two products is due to the increased aqueous solubility
`of the sodium salt of naproxen used in ANAPROX. Peak
`plasma levels of naproxen given as NAPROSYN Suspension
`are attaint in 1 to 4 hours.
`Delayed Release: EC-NAPROSYN is designed with a pH-
`sensitive coaling to provide a barrier to disintegration in the
`acidic environment of the stomach and to lose integrity in
`the more neutral environment of the small intestine. The
`enteric polymer coating selected for EC-NAPROSYN dis­
`solves above pH 6. When EC-NAPROSYN was given to
`fasted subjects, peak plasma levels were attained about 4 to _
`6 hours following the first dose (range: 2 to 12 hours). An in
`vivo study in man using radiolabeled EC-NAPROSYN tab­
`lets demonstrated that EC-NAPROSYN dissolves primarily
`in the small intestine rather than the stomach, so the ab­
`sorption of the drug is delayed until the stomach is emptied.
`When EC-NAPROSYN and NAPROSYN were given to
`fasted subjects (n=24) in a crossover study following 1 week
`of dosing, differences in lime to peak plasma levels (T,„„)
`were observed, but there were no differences in total absorp­
`tion as measured by C„aK AUC:
`[See table at top of next pagel
`Antacid Effects: When EC-NAPROSYN was given as a sin­
`gle dose with antacid (54 mEq buffering capacity), the peak
`plasma levels of naproxen were unchanged, but the time to
`peak was reduced (mean To,*, fasted 5.6 hours, mean Tn,*,
`with antacid 5 hours), although not significantly.
`Food Effects: When EC-NAPROSYN was given as a single
`dose with food, peak plasma levels in most subjects were
`achieved in about 12 hours (range: 4 to 24 hours). Residence
`time in the small intestine until disintegration was inde­
`pendent of food intake. The presence of food prolonged the
`time the tablets remained in the stomach, time to first de­
`tectable scrum naproxen levels, and time to maximal
`naproxen levels (?„,„), but did not affect peak naproxen lev­
`els (C„,„).
`Dis/riburion:
`Naproxen has a volume of distribution of 0.16 IVkg. At ther­
`apeutic levels naproxen is greater than 99% albumin-
`bound. At doses of naproxen greater than 500 mg/day there
`is less than proportional increase in plasma levels due to an
`increase in clearance caused by saturation of plasma pro­
`tein binding at higher doses (average trough C„ 36.5, 49.2
`and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of
`naproxen). However, the concentration of unbound
`naproxen continues to increase proportionally to dose.
`Afe/a6o//sm.*
`Naproxen is extensively metabolized to 6-0-desmethyl
`naproxen, and both parent and metabolites do not induce
`metabolizing enzymes.
`Elimination:
`The clearance of naproxen is 0.13 mL/min/kg. Approxi­
`mately 95% of the naproxen from any dose is excreted in the
`urine, primarily as naproxen (less than 1%). 6-0-desmethyl
`naproxen (less than 1%) or their conjugates (66% to 92%).
`The plasma half-life of the naproxen anion in humans
`ranges from 12 to 17 hours. The corresponding half-lives of
`both naproxen’s metabolites and conjugates are shorter
`than 12 hours, and their rotes of excretion have been found
`to coincide closely with the rate of naproxen disappearance
`from the plasma. In patients with renal failure metabolites
`may accumulate. .
`Special Populations:
`Pediatric Patients: In pediatric patients aged 5 to 16 years
`with arthritis, plasma naproxen levels following a ®
`single dose of naproxen suspension (see DOSAGE AND
`MINISTRATION) were found to be similar to those found m
`normal adults following a 500 mg dose. The terminal half-
`life appears to be similar in pediatric and adult pallets.
`Pharmacokinetic studies of naproxen were not performed in
`pediatric patients younger than 5 years of age. Pharmaco­
`kinetic parameters appear to be similar following adminis­
`tration of naproxen suspension or tablets in pediatric pa­
`tients. EC-NAPROSYN has not been studied in subjects un­
`der the age of 18. .
`.
`Renal Insufficiency: Naproxen pharmacokinetics has not
`been determined in subjects with renal insufficiency. Given
`that naproxen, its metabolites and conjugates ore primaniy
`excreted by the kidney, the potential exists for naproxen i^-
`tabolites to accumulate in the presence of renal insuffi­
`ciency.
`CLINICAL STUDIES
`Genera/ Information: Naproxen has been studied in pa­
`tients with rheumatoid arthritis, osteoarthritis, juvenile ar-
`thrilis, ankylosing spondylitis, tctidonitis and bursitis, and
`acute gout. Improvement in patients treated for rheumatoid
`arthritis was demonstrated by a reduction in joint swelling.
`Continued on next page
`Consult 2000 PDR' supplements and future etfrtions for revisions
`
`I
`
`EC-NAPROSYN®
`(naproxen)
`Detayed-Release Tablets
`NAPROSYN®
`(naproxen)
`Tablets
`ANAPROX®/ANAPROX® DS
`[an' d-prox)
`(naproxen sodium)
`Tablets
`NAPROSYN®
`(neproxen)
`Suspension
`The following text is complete prescribing information
`based on official labeling in effect June 1999,
`DESCRIPTION
`Naproxen is a member of the arylacetic acid group of non­
`steroidal anti-inflammatory drugs.
`The chemical names for naproxen and naproxen sodium are
`(S)-6-methoxy-a-mcthyl-2-naphthaleneacetic acid and (S)-6-
`mcthoxy-a-methyl-2-naphlhaleneacetic acid, sodium salt,
`respectively.
`Naproxen is an odorless, white to off-white crystalline sub­
`stance. It is lipid-soluble, practically insoluble in water at
`low pH and freely soluble in water at high pH. The octanol/
`water partition coefficient of naproxen at pH 7.4 is 1.6 to
`1.8. Naproxen sodium is a white to creamy white, crystal­
`line solid, freely soluble in water at neutral pH.
`NAPROSYN (naproxen) Tablets contain 250 mg, 375 mg or
`500 mg of naproxen and croscarmellose sodium, iron oxides,
`povidone and magnesium stearate.
`EC-NAPROSYN (naproxen) Delayed-Release Tablets are
`enteric-coated tablets containing 375 mg or 500 mg of
`naproxen and croscarmellose sodium, povidone and magne­
`sium stearate. The enteric coating dispersion contains
`methacrylic acid copolymer, talc, triethyl citrate, sodium hy­
`droxide and purified water. The dispersion may also contain
`simethicone emulsion. The dissolution of this enteric-coated
`naproxen tablet is pH dependent with rapid dissolution
`above pH 6. There is no dissolution below pH 4.
`Each ANAPROX 275 mg and ANAPROX DS 550 mg tablet
`contains naproxen sodium, the active ingredient, with mag­
`nesium stearate, microcry'slalline cellulose, povidone and
`talc. The coating suspension for the ANAPROX 275 mg tab­
`let may contain hydroxypropyl methylcellulose 2910,
`Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry
`YS-1-4216. The coating suspension fbr the ANAPROX DS
`550 mg tablet may contain hydroxypropyl methylcellulose
`2910, Opaspray K-1-4227, polyethylene glycol 8000 or
`Opadry YS-1-4216.
`NAPROSYN (naproxen) Suspension for oral administration
`contains 125 mg/5 mL of naproxen in a vehicle containing
`sucrose, magnesium aluminum silicate, sorbitol solution
`and sodium chloride (30 mg/5 mL, 1.5 mEq), raelhylpara-
`ben, fumaric acid, FD&C Yellow No. 6, imitation pineapple
`flavor, imitation orange flavor and purified water. *1116 pH of
`the suspension ranges from 2.2 to 3.7.
`CLINICAL PHARMACOLOGY
`Naproxen is a ' nonsteroidal anti-inflammatory drug
`(NSAID) with analgesic and antipyretic properties. The so­
`dium salt of naproxen has been developed as o more rapidly
`absorbed formulation of naproxen for use as an analgesic.
`The naproxen anion inhibits prostaglandin synthesis but
`beyond this its mode of action is unknown.
`Pharmacok/netfcs: Naproxen itself is rapidly and com­
`pletely absorbed from the gastrointestinal tract with an in
`vivo bioavailability of 95%. The different dosage forms of
`NAPROSYN are bioequivalent in terms of extent of absorp­
`tion (AUC) and peak concentration (C„,,,); however, the
`products 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 formulation. Even
`with the observed differences in pattern of absorption, the
`
`tients may be sm dEMADEX intravenous injection
`
`-J tj,o potential for incompatibilities caused
`^
`could bo indicated by color
`mended to
`changt ha" iness
`*''■= »»-
`
`temperature in plastic containers for the following fluids
`
`2,50 mL Dextrose 5%
`SorgSEMlDEXdOm^mUaddedto:
`Dextrose 5» in water
`^SmL045%to!irm“de
`
`u'rarS to'approxiltely doubling until the desired di-
`ufre res^nL is obtained Single doses higher than 200
`initial dose of
`dImaDEX is 20 mg of oncc-daily oral or intravenous
`npM ^npV If the diuretic response is inadequate, the dose
`°h?u^^b^ grated upward by approwmately doubling until
`LVXf flUo m^UTnotU fd^tlyltd''""’
`;/e 1% CirrAol The usual initial dose is 5 mg or 10 mg
`ofonre da^ly oral or intravenous DEMADEX, administered
`with on aldosterone antagonist or a potassium-
`snarine drurotic. If the diuretic response is inadequate, the
`dose should bo titrated upward by approximately doubling
`until the desired diuretic response is obtained. Single doses
`higher than 40 mg have riot boon odoquatoly studied
`Chiainic use of any diuretic in hepatic disease has not been
`stored in adequate and woll^ontrelled trials.
`f/Jirlension.- The usual initial dose is 5 mg once doily. If
`UteG mg dose does not provide adequate reduction in blood
`D»,s„re within 4 to 6 weeks, the dose may be increased to
`10 mg once daily. If the response to 10 mg is insufficient, on
`addTtional anlihypertonsivo agent should bo added to the
`treatment regimen.
`How SUPI’DIED
`DEMADEX for oral administration is available os white,
`scored tablets containing 6 mg, 10 mg, 20 mg, or 100 mg of
`torsemide The tablets arc supplied in holllos and Tbl-E-
`Dose®- packages of 100 os follows:
`iSce tnblo above)
`Each tablet is debossed on the scored side with the
`Bochringcr Mannheim logo and 102, 103, 104, or 105 (for 5
`
`MYLAN PHARMS. INC. EXHIBIT 1088 PAGE 5
`
`

`

`PHYSICIANS' DESK REFERENCE®
`NAPROSW
`500 mg bid
`97.4(13^0
`1.9 (61%)
`767 (15%)
`
`EC-NAPROS'^'N*
`500 mg bid
`Ol.OdflCr)
`4 (39% )
`845 (20%)
`
`2632/ROCHE LABORATORIES
`EC-Naprosyn/Anaprox—Cont.
`
`C„„(Mg/mL)
`Tpiax (hours)
`AUCo_i2hr (pg’br/mL) •
`
`a reduction in duration of morning stiffness, a reduction in
`disease activity as assessed by both the investigator and pa­
`tient, and by increased mobility as demonstrated by a re­
`duction in walking time. Generally, response to naproxen
`has not been found to be dependent on age. sex. severity or
`duration of rheumatoid arthritis.
`Analgesia/Oysmenorrhea/Bursitis and Tendonitis: Be­
`In patients'with osteoarthritis; the therapeutic action of
`cause the sodium salt of naproxen is more rapidly absorbed,
`naproxen has been shown by a reduction in joint pain or
`ANAPROX/ANAPROX DS is recommended for the manage­
`tenderness, an'increasc in range of motion in knee joints,
`ment of acute painful conditions when prompt onset of pain
`increased mobility as demonstrated by a reduction in walk­
`relief is derired. The recommended starting dose is 550 mg
`ing time, and improvement in capacity to perform activities
`followed by 550 mg every 12 hours or 275 mg every G to 8
`of daily living impaired by the disease.
`hours, as required. The initial total daily dose should not
`In a clinical trial comparing standard-formulations of
`exceed 1375 mg of naproxen sodium. Thereafter, the total
`naproxen 375 mg bid (750 mg a day) vs 760 mg bid (1500
`daily dose should not exceed 1100 mg of naproxen sodium.
`mg/day), 9 patients in the 750 mg group terminated prema­
`NAPROSYN may also be used for treatment of acute pain
`turely ^cause of adverse events. Nineteen' patients in the
`and dysmenorrhea. EC-NAPROSYN is not recommended
`1500 mg group terminated prematurely because of adverse
`for initial treatment of acute pain because absorption of
`events. Most of these adverse events were gastrointestinal
`naproxen is delayed compared to other naproxen-containing
`events.
`products (see CLINICAL PHARMACOLOGY and INDICA­
`In clinical studies in patients with rheumatoid arthritis, os-
`TIONS AND USAGE).
`teoarthritis and juvenile arthritis, naproxen has been
`Acute Gout: The recommended starting dose is 750 mg of
`shown to be comparable to aspirin and indomethacin in con­
`NAPROSYN followed by 250 mg every 8 hours until the at­
`trolling the aforementioned measures of disease activity,
`tack has subsided. ANAPROX may also be used nt a starl­
`but the frequency and severity of the milder gastrointesti­
`ing dose of 825 mg followed by 275 mg every 8 hours as
`nal adverse effects (nausea, dyspepsia, heartburn) and ner­
`needed. EC-NAPROSW Is not recommended because of the
`vous system adverse effects (tinnitus, dizziness. lighthead­
`delay in absorption (see CLINICAL PHARMACOLOGY).
`edness) were less in naproxen-treated patients than in
`Osteoarthritis/Rheumato'id Arthritis/Ankylosing Spondyli­
`those.treated with aspirin or indomethacin.
`tis: The recommended dose of naproxen is NAPROS^’N or
`In patients with ankylosing spondylitis, naproxen has been
`NAPROSYN Suspension 250 mg, 375 mg or 500 mg taken
`shown to decrease night pain, morning stiffness and pain at
`twice d.aily (morning and evening) or EC-NAPROSYN 375
`rest. In double-blind studies the drug was shown to be as
`mg or 500 mg taken twice daily. Naproxen sodium may also
`effective as aspirin, but with fewer side effects.
`be used (see DOSAGE AND ADMINISTRATION).
`In patients with acute gout, a favorable response to
`During long-term administration the dose of naproxen may
`naproxen was shown by significant clearing of.inflamraatory
`be adjusted up or down depending on the clinical response
`changes (eg, decrease in swelling, heat) within 24 to 48
`of the patient. A lower daily dose may suffice for long-term
`hours, a.s well as by relief of pain and tenderness.
`administration. In patients who tolerate lower doses well,
`the dose may be increased to 1500 mg per day when a
`Naproxen has been studied in patients with mild to moder­
`higher level of anti-inflammatory/analgesic activity is re­
`ate pain secondary to postoperative, orthopedic, postpartum
`quired. When treating patients with naproxen 1500 mg/day
`episiotomy and uterine contraction pain and dysmenorrhea.
`(as NAPROSYN or 1650 mg.of ANAPROX), the physician
`Onset of pain relief can begin within 1 hour in patients tak­
`ing naproxen and within 30 minutes in patients taking
`should observe sufficient increased clinical benefit to offset
`the potential increased risk. The morning and evening
`naproxen sodium. Analgesic effect was shown by such meas­
`doses do not have to be equal in size and administration of
`ures as reduction of pain intensity scores, increase in pain
`the drug more frequently than twice daily docs not gener­
`relief scores, decrease in numbers of patients requiring ad­
`ally make a difference in response (see CLINICAL PHAR­
`ditional analgesic medication, and delay in time to reraedi-
`cation. The analgesic effect has been found to last for up to
`MACOLOGY).
`Juvenile Arthritis: The use of NAPROSYN Suspension al­
`12 hours.
`lows for more flexible dose titration. In pediatric patients,
`Naproxen inay be used safely in combination with gold salts
`doses of 5 mg/kg/day produced plasma levels of naproxen
`and/or corticosteroids; however, in controlled clinical trials,
`similar to those seen in adults taking 500 mg of naproxen
`when added to the regimen of patients receiving corticoster­
`(see CLINICAL PIURMACOLOGY).
`oids, it did not appear to cause greater improvement over
`The recommended total daily dose is approximately 10
`that seen with corticosteroids alone. Whether naproxen has
`mg/kg given in two divided doses (ie, 5 mg/kg given twice a
`a “Steroid-sparing” effect has not been adequately studied.
`When added to the regimen of patients receiving gold salts,
`day) (see DOSAGE AND ADMINISTRATION).
`naproxen did result in greater improvement. Its use in com­
`INDICATIONS AND USAGE
`bination with salicylates is not recommended because there
`Naproxen as NAPROSYN. EC-NAPROSYN. ANAPROX,
`is evidence that aspirin increases the rate of excretion of
`ANAPROX DS or NAPROSYN Suspension ore indicated for
`naproxen and data are inadequate to demonstrate that
`the treatment of rheumatoid arthritis, osteoarthritis, anky­
`naproxen and a.spirin produce greater improvement over
`losing spondylitis and juvenile arthritis.
`that achieved with aspirin alone. In addition, as with other
`Naproxen as NAPROSYN Suspension is recommended for
`NSAIDs, the combination may result in higher frequency of
`juvenile rheumatoid arthritis in order to obtain the maxi­
`adverse events than demonstrated for either product alone.
`mum dosage flexibility based on the patient’s weight.
`In blood loss and gastroscopy studies with normal vol­
`Naproxen as NAPROSYN. ANAPROX, ANAPROX DS and
`unteers, daily administration of 1000 mg of naproxen as
`NAPROSYN Suspension are also indicated for the treat­
`1000 mg of NAPROSYN (naproxen) or 1100 mg of
`ment of tendinitis, bursitis, acute gout, and for the manage­
`ANAPROX (naproxen sodium) has been demonstrated to
`ment of pain and primary dysmenorrhea. EC-NAPROS")^
`cause statistically significantly less gastric bleeding and
`is not recommended for initial treatment of acute pain be­
`erosion than 3250 mg of aspirin.
`cause the absorption of naproxen is delayed compared to ab­
`Three 6-week,. double-blind, multicenter studies with
`sorption from other naproxen-containing products (see
`EC-NAPROSYN (naproxen) (375 or 500 mg bid, n=385) and
`CLINICAL PHARMACOLOGY and DOSAGE AND AD­
`NAPROSYN (375 or 500 mg bid, n=279) were conducted
`MINISTRATION). .
`comparing EC-NAPROSYN with NAPROSYN, including
`355 rheumatoid arthritis and osteoarthritis patients who
`CONTRAINDICATIONS
`had a recent history of NSAID-related GI symptoms. These
`All naproxen products are contraindicated in patients who
`studies indicated that EC-NAPROSYN and NAPROSYN
`have had allergic reactions to prescription as well as to over-
`showed no significant differences in efficacy or safety and
`the-counter products containing naproxen. It is also contra­
`had similar prevalence of minor GI complaints. Individual
`indicated in patients in whom aspirin or other nonsteroidal
`patients; however, may.find one formulation preferable.to
`anti-inflammatory/analgesic drugs induce the syndrome of
`tile other. ;
`asthma, rhinitis and nasal polyps. Both types of reactions
`Five hundred arid fifty-three' patients received
`have the potential of being fatal. Anaphylactoid reactions to
`EC-N^rOSYN during long-term open label trials (mean
`naproxen, whether of the true allergic type or the pharma­
`length of treatment was 159 days). Tbe rates for clinically-
`cologic idiosyncratic (eg, aspirin hypersensitivity syndrome)
`diagnosed peptic ulcers and GI bleeds were similar to what
`usually but not always occur in patients with a knowm
`has been historically reported for long-term NSAID use.
`history of such reactions. Therefore, careful questioning of
`INDIVIDUAUZATION OF DOSAGE
`patients for such things os asthma, nasal polyps, urticaria
`^though- NAPROSYN, ' NAPROSYN Suspension,
`and hypotension associated with nonsteroidal anti-inflam­
`EC-NAPROSYN, ANAPROX and ANAPROX DS all circu-
`matory drugs before starting therapy is important. In addi­
`late in the plasma as naproxen, they have pharmacokinetic
`tion, if such symptoms occur during therapy, treatment
`differences that may affect onset of action. Onset of pain re-
`should be discontinued.
`lief can begin within 30 minutes in patients taking
`WARNINGS
`naproxen sodium and within 1 hour in patients taking
`Risk of GI Ulceration, Bleeding and Perforation with NSAID
`naproxen. Because EC-NAPROSYN dissolves in the small
`Therapy: Serious gastrointestinal toxicity such os bleed­
`intestine rather than in the stomadi, the absorption of the
`ing, ulceration and perforation can occur at any time, with
`drug is delayed compared to the other naproxen formula­
`or without warning symptoraa, in patients treated chroni­
`tions (see CLINICAL PHARMACOLOGY).
`cally with NSAID therapy. Although minor upper gastroin­
`The recommended strategy for initiating therapy is to
`testinal problems, such as dyspepsia, ore common, usually
`choose a formulation and a starting dose likely to be effec­
`developing early in therapy, physicians should remain alert
`tive for the patient and then adjust the dosage based on ob­
`for ulceration and bleeding in patients treated chronically
`servation of benefit and/or adverse events. A lower dose
`with NSAIDs even in the absence of previous GI tract symp­
`ishould be considered in patients with renal or hepatic im­
`toms. In patients observed in clinical trials of several
`pairment or in elderly patients (see PRECAUTIONS).
`months to 2 years’ duration, symptomatic upper GI ulcers.
`Information will be superseded by supplements and subsequent editions
`
`gross bleeding or perforation appear to occur in opp.w.
`mutely Vr,. of patients treated for 3 to G months and in oooui
`27,. to 4'r. of patients treated for 1 year.
`Physicians should inform patients about the signs amPor
`symptoms of serious GI toxicity and what steps to taxc i
`Studi°es't'o date with all naproxen products have not identi­
`fied any subset of patients not nt risk of dnveloping^pw
`ulceration and bleeding or any differences between different
`naproxen products in their propensity to cause KP “
`alion and bleeding. Except for a prior history
`events and other risk factors known to be “located witn
`peptic ulcer disease, such as alcoholism, smokmg.
`risk factors (eg, age, sex) have been associated with i •
`creased risk. Elderly or debilitated patients seem to tolerate
`ulceration or bleeding less well than other
`most spontaneous reports of fatal GI events arc in this i»p-
`ulation. Studies to date arc inconclusive concerning the r
`ative risk of various NSAIDs in causing such reactions^
`High doses of anv NSAID probably carry a greater nsK oi
`these reactions, although controlled clinical trials showing
`this do not exist in most cases. In considering the use o! rci
`otively large doses (within the recommended dosage rangcJ.
`sufficient benefit should be anticipated to offset the poten­
`tial increased risk of GI toxicity.
`PRECAUTIONS
`General:
`NAPROXEN-CONTAINING PRODUCTS SUCH
`AS NAPROSYN. EC-NAPROSYN. ANAPROX. ANAPROX Db.
`NAPROSYN SUSPENSION. ALEVE®*. AND OTHfc«
`NAPROXEN PRODUCTS SHOULD NOT BE USED CONCOM­
`ITANTLY SINCE THEY ALL CIRCULATE IN THE PLASMA Ab
`THE NAPROXEN ANION.
`If the steroid dose is reduced or eliminated during therapy,
`the stero