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`Page 1 Dr. Reddy's Exh. 1063
`
`

`

`PRODUCT INFORMATION
`
`Dose
`5 mg
`10 mg
`20 mg
`100 mg
`
`Shape
`oval
`oval
`oval
`capsule-shaped
`
`Bott/c
`NDC 0004-0262-01
`NDC 0004-0263-01
`NDC 0004-0264-01
`NDC 0004-02GG-01
`
`Tc/-E-Dose
`NDC 0004-0262-49
`NDC 0004-0263-49
`NDC 0004-0264-49
`NDC 0004-02G5-49
`
`in a patient
`has been reported
`exposed to
`Angioedema
`DEMADEX who was later
`found to be allergic to sulfa
`drugs.
`trials
`reactions during placebo-controlled
`Of the adverse
`of related-
`listed without
`taking mto account assessment
`and various other nonspecific
`ness to drug therapy, arthritis
`reported in
`musculoskeletal
`problems were more frequently
`association with DEMADEX than with
`even
`placebo,
`though gout was somewhat more frequently associated with
`placebo. These reactions did not increase in frequency or se-
`verity with the dose of DEMADEX. One patient
`in the group
`and one
`treated with DEMADEX withdrew due to myalgia,
`in the placebo group withdrew due to gout.
`See WARNINGS.
`Hypohoiemiu.
`OVERDOSAGE
`of
`There
`is
`overdoses
`experience
`with
`human
`no
`DEMADEX, but the signs and symptoms of overdosage can
`be anticipated to be those of excessive pharmacologic
`effect:
`hyponatremia,
`hy-
`dehydration,
`hypotension,
`hypovolemia,
`and hemoconcentra-
`alkalosis,
`pokalemia,
`hypochloremic
`should consist of fluid and
`tion. Treatment of overdosage
`electrolyte replacement.
`of serum levels of torsemide and
`Laboratory determinations
`are not widely available.
`its metabolites
`No data are available
`to suggest physio)agree) maneuvers
`that might
`to change the pH of the unne)
`(eg, maneuvers
`and its metabolites.
`of torsemide
`accelerate elimmation
`so hemodialysis will not accel-
`Torsemide is not dialyzable,
`erate elimination.
`DOSAGE AND ADMINISTRATION
`DEMADEX tablets may be given at any time in
`General
`relation to a meal, as convenient Special dosage adjustment
`in the elderly is not necessary.
`Because of the high bioavailabihty
`of DEMADEX, oral and
`doses are therapeutically
`intravenous
`equivalent,
`so pa-
`tients may be switched to and from the intravenous
`form
`with no change in dose. DEMADEX intravenous m)ection
`slowly as a bolus over a pe-
`either
`should be administered
`as a continuous
`nod of 2 minutes or administered
`infusion.
`If DEMADEX is administered
`it is rec-
`through an IV line,
`that, as with other
`the IV line be
`IV fn)ecttons,
`ommended
`Injection,
`flushed with Normal Saline (Sodium Chloride
`USP) before and after administration. DEMADEX injection
`above pH 8.3. Flushmg
`the line is recom-
`is formulated
`caused
`mended to avoid the potential
`for incompatibilities
`by color
`in pH which could be indicated
`by differences
`change, haziness or the formation of a precipitate
`in the so-
`lution.
`If DEMADEX is administered
`infusion, sta-
`as a continuous
`24 hours at room
`bility has been demonstrated
`through
`for the following
`in plastic containers
`temperature
`fluids
`and concentrations:
`200 mg DEMADEX (10 mg/mL)
`250 mL Dextrose 5% in water
`250 mL 0.9% Sodium Chloride
`500 mL 0.45% Sodium Chloride
`added to:
`50 mg DEMADEX (10 mg/mL)
`500 mL Dextrose 5'/o in water
`500 mL 0.9% Sodium Chloride
`500 mL 0 45'/o Sodium Chloride
`the solution of DEMADEX should be
`Before administration,
`and particulate matter
`visually inspected for discoloration
`If either
`should not be used.
`the ampul
`is found,
`initial dose is 10 mg
`The usual
`Cougestiue Heart Fui/urc:
`or 20 mg of once-daily oral or intravenous DEMADEX. Ifthe
`the dose should be titrated
`diuretic response is inadequate,
`the desired di-
`doubling until
`by approximately
`upward
`than 200
`is obtained. Single doses higher
`uretic response
`studied.
`mg have not been adequately
`of
`usual mitial
`Failure.
`Chronic Renal
`dose
`The
`DEMADEX is 20 mg of once-daily
`oral or intravenous
`DEMADEX. If the diuretic response is inadequate,
`the dose
`doubling until
`should be titrated upward by approximately
`is obtained. Single doses
`response
`the desired diuretic
`than 200 mg have not been adequately
`studied
`higher
`initial dose is 5 mg or 10 mg
`Hepatic Cirrhosis:
`The usual
`of once-daily oral or intravenous DEMADEX, administered
`or a potassium-
`together with an aldosterone
`antagonist
`sparing diuretic. If the diuretic response is inadequate,
`the
`dose should be titrated upward by approximately
`doublmg
`Single doses
`the desired diuretic response is obtmned
`until
`than 40 mg have not been adequately
`studied.
`higher
`Chronic use of any diuretic in hepatic disease has not been
`trials.
`and well-controlled
`studied in adequate
`initial dose is 5 mg once daily. If
`The usual
`tension
`Hypei
`the 5 mg dose does not provide adequate
`reduction in blood
`the dose may be increased to
`pressure within 4 to 6 weeks,
`10 mg once daily If the response to 10 mg is msuflicient,
`an
`should be added to the
`agent
`antihypertensive
`additional
`treatment
`regimen
`HOW SUPPLIED
`as white,
`DEMADEX for oral administration
`is available
`scored tablets containmg 5 mg, 10 mg, 20 mg, or 100 mg of
`in bottles and Tel-E-
`torsemide. The tablets are supplied
`Dose* packages of 100 as follows:
`(See table above)
`is debossed
`Each tablet
`the
`on the scored side with
`Boehringer Mannheim logo and 102, 103, 104, or 105 (for 5
`
`added to:
`
`mg, 10 mg, 20 mg, or 100 mg, respectively). On the opposite
`side, the tablet
`is debossed with 5, 10, 20, or 100 to mdicate
`the dose.
`
`injection is supplied
`DEMADEX for mtravenous
`in clear
`contaming 2 mL (20 mg, NDC 0004-0267-06) or 5
`ampule
`mL (50 mg, NDC 0004-0268-06) of a 10 mg/mL sterile solu-
`tion.
`Storage: Store all dosage forms at 15'o 30'C (59'o 86'F).
`Do not fieeze.
`
`trademark
`
`of Hoffmann-La
`
`"Tel-E-Dose is a registered
`Roche Inc.
`Tablets manufactured
`by:
`Boehringer Mannheim, GmbH, Mannheim, Germany
`Ampule manufactured
`by.
`Abbott Laboratones, North Chicago, IL 60064
`Revised; April 1998
`Shoion iu Pi oduct Itfcuttficutton Guide, page 334
`
`EC-NAPROSYN
`(naproxen)
`Delayed-Release Tablets
`
`NAPROSYN
`(naproxen)
`Tablets
`
`ANAPROX/ANAPROX(flf
`[un'-prox)
`(naproxen sodium)
`Tablets
`
`OS
`
`NAPROSYN
`(naproxen)
`Suspension
`
`information
`
`text
`prescribing
`is complete
`labeling in effec June 1999.
`
`The following
`based on official
`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
`acid and (S)-6-
`(S)-6-methoxy-a-methyl-2-naphthaleneacetic
`acid, sodium salt,
`methoxy-u-methyl-2-naphthaleneacetic
`respectively.
`sub-
`Naproxen is an odorless, white to ofl'-white crystalhne
`in water at
`stance. It is lipid-soluble,
`practically insoluble
`low pH and freely soluble in w'ster at high pH The octanoV
`at pH 7.4 is 16 to
`water partition coefficient of naproxen
`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
`iron oxides,
`sodium,
`and magnesium stearate.
`povidone
`EC-NAPROSYN (napioxen) Delayed-Release Tablets are
`375 mg or 500 mg of
`tablets
`enteric-coated
`containing
`sodium, povidone and magne-
`naproxen and croscarmellose
`sium stearate. The enteric coating dispersion
`contains
`talc, triethyl mtrate, sodium hy-
`acid copolymer,
`methacrylic
`droxide and purified water. The dispersion may also contain
`emulsion. The dissolution of this entenc-coated
`simethicone
`tablet
`is pH dependent with rapid dissolution
`naproxen
`below pH 4.
`above pH 6. There is no dissolution
`Each ANAPROX 275 mg and ANAPROX DS 550 mg tablet
`the active ingredient, with mag-
`contams naproxen sodium,
`nesium stearate, microcrystalhne
`and
`cellulose, povidone
`talc. The coating suspension for the ANAPROX 275 mg tab-
`2910,
`let may
`contain
`methylcellulose
`hydroxypropyl
`Opaspray K-1-4210A, polyethylene
`glycol 8000 or Opadry
`YS-1-4215. The coating suspension
`for 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 sdicate,
`solution
`sorbitol
`(30 mg/5 mI., 1.5 mEq), methylpara-
`and sodium chloride
`ben, fumaric acid, FD&C Yellow No. 6, imitation pmeapple
`imitation orange flavor and punfied water. The pH of
`flavor,
`ranges from 2.2 to 3.7.
`the suspension
`CLINICAL PHARMACOLOGY
`a nonsteroidal
`is
`anti-inflammatory
`Naproxen
`drug
`(NSAID) with analgesic and antipyretic properties. The so-
`dium salt of naproxen has been developed as a more rapidly
`for use as an analgesic
`of naproxen
`absorbed formulation
`anion mhibits prostaglandin
`synthesis
`The naproxen
`but
`beyond this its mode of action is unknown.
`itself is rapidly and com-
`Pharmaookinetics:
`Naproxen
`tract with an in
`pletely absorbed from the gastrointestinal
`of 95%. The different dosage forms of
`vivo bioavailability
`in terms of extent of absorp-
`NAPROSYN are bioequivnlent
`the
`tion (AUC) and peak concentration
`(Cmo„); however,
`products do differ in their pattern of absorption. These dif-
`ferences between naproxen products are related to both the
`used and its formulation. Even
`form of naproxen
`chemical
`in pattern of absorption,
`the
`with the observed difFerences
`
`ROCHE LABORATORIES/2631
`
`across prod-
`half-hfe of naproxen is unchanged
`elimination
`levels of
`from 12 to 17 hours. Steady-state
`ucts ranging
`are reached in 4 to 5 days, and the degree of
`naproxen
`is consistent with this half-life. This
`naproxen accumulation
`in pattern of release play only
`that
`the differences
`suggests
`a neghgtble
`of steady-state
`role in the attainment
`plasma
`levels.
`Absorption;
`of NAPROSYN
`After adnnnistration
`ImrneCkute Release:
`tablets, peak plasma levels are attamed m 2 to 4 hours. Af-
`ter oral admimstration
`levels
`of ANAPROX, peak plasma
`are attained in 1 to 2 hours. The difierence in rates between
`is due to the increased aqueous
`solubility
`the two products
`used in ANAPROX Peak
`of the sodium salt of naproxen
`plasma levels of naproxen given as NAPROSYN Suspension
`are attained in 1 to 4 hours.
`EC-NAPROSYN is designed with a pH-
`Delayed Release:
`in the
`sensitive coating to provide a barrier to disintegration
`of the stomach and to lose integrity in
`acidic environment
`of the small mtestine. The
`environment
`the more neutral
`coating selected for EC-NAPROSYN, dis-
`enteric polymer
`solves above pH 6. When EC-NAPROSYN was given to
`fasted sub)ects, 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-
`that EC-NAPROSYN dissolves pnmanly
`lets demonstrated
`so the ab-
`rather
`than the stomach,
`intestine
`in the small
`the stomach is emptied.
`sorption of the drug is delayed until
`When EC-NAPROSYN and NAPROSYN were given to
`fasted sub)ects (n=24) m a crossover study following I week
`levels (T„„,)
`of dosmg, differences
`in time to peak plasma
`were obseived, but there were no differences m total absorp-
`tion as measured by C„,„andAUC:
`[See table at top of next page]
`Antacid Effects: When EC-NAPROSYN was given as a sin-
`the peak
`gle dose with antacid (54 mEq bufFenng capacity),
`but the time to
`plasma levels of naproxen were unchanged,
`
`peak was reduced (mean Tw„„fasted 5.6 hours, mean T„,„„
`
`with antacid 5 hours), although not significantly.
`Food Effects: When EC-NAPROSYN was given as a single
`in most subjects were
`levels
`dose with food, peak plasma
`achieved in about 12 hours (range: 4 to 24 hours). Residence
`until disintegration was inde-
`intestine
`time in the small
`the
`pendent of food intake. The presence of food prolonged
`time to first de-
`time the tablets remained in the stomach,
`and time to maximal
`levels,
`serum naproxen
`tectable
`naproxen levels (T„,~),but did not affect peak naproxen lev-
`els (C,„).
`Distributioni
`of 0.16I/kg. At ther-
`Naproxen has a volume of distribution
`than 99% albumin-
`is greater
`levels naproxen
`apeutic
`than 500 mg/day
`there
`bound. At doses of naproxen greater
`increase in plasma levels due to an
`is less than proportional
`mcrease m 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
`of unbound
`concentration
`the
`naproxen).
`However,
`to dose
`to increase proportionally
`naproxen continues
`Metabolism.
`to 6-0-desmethyl
`is extensively metabolized
`Naproxen
`do not
`and metabolites
`induce
`and both parent
`naproxen,
`enzymes.
`metabolizing
`
`Elimination'he
`
`is 0.13 mL/min/kg. Approxi-
`clearance of naproxen
`mately 95% of the naproxen from any dose is excreted in the
`as naproxen (less than 1%), 6-0-desmethyl
`urine, pnmarily
`(66% to 92%o)
`naproxen (less than I'/o) or their conjugates
`anion in humans
`The plasma half-life of the naproxen
`half-lives of
`ranges from 12 to 17 hours. The corresponding
`are shorter
`and con)ugates
`both naproxen's metabolites
`than 12 hours, and their rates of excretion have been found
`to coinmde closely with the rate of naproxen disappearance
`failure metabolites
`In patients with renal
`from the plasma.
`may accumulate.
`Special Populations:
`In pediatnc patients aged 5 to 16 years
`Pediatne Patients:
`with arthritis, plasma naproxen levels following a 5 mg/kg
`single dose of naproxen suspension (see DOSAGE AND AD-
`to those found in
`MINISTRATION) were found to be similar
`normal adults following a 500 mg dose. The terminal half-
`and adult patients,
`in pediatric
`to be similar
`life appears
`studies of naproxen were not performed in
`Pharmacokinetic
`than 5 years of age. Pharmaco-
`pediatric patients younger
`following admmis-
`to be similar
`appear
`kinetic parameters
`or tablets
`in pediatnc pa-
`tration of naproxen suspension
`tients. EC-NAPROSYN has not been studied in sub)sets un-
`der the age of 18.
`has not
`pharmacokinetics
`Naproxen
`Renal
`Insu/ficicncy.
`insufflciency. Given
`been determined m sub)ects with renal
`and con)ugates are primarily
`its metabolites
`that naproxen,
`the potential crusts for naproxen me-
`excreted by the kidney,
`in the presence of renal
`tnsuffi-
`to accumulate
`tabolites
`ciency.
`CLINICAL STUDIES
`has been studied in pa-
`Naproxen
`tn/ormationt
`Genera/
`ar-
`arthntis, osteoarthritis,)uvenile
`tients with rheumatoid
`and bursitis, and
`tendomtis
`spondyhtis,
`thritis, ankylosing
`in patients treated for rheumatoid
`Improvement
`acute gout
`by a reduction in joint swelling,
`arthntis was demonstrated
`
`Continued on next page
`
`Page 2 Dr. Reddy's Exh. 1063
`
`

`

`2632/ROCHE LABORATORIES
`
`EC-NGPTOSyn/AnaPTOX —Cont.
`
`a reduction in duration of morning sti(Fness, a reduction in
`and pa-
`disease activity as assessed by both the investigator
`by a re-
`tient, and by increased mobility as demonstrated
`to naproxen
`response
`duction in walking time. Generally,
`on age, sex, severity or
`has not been found to be dependent
`arthritis
`duration of rheumatoid
`action of
`the therapeutic
`In patients with osteoarthritis,
`naproxen has been shown by a reduction in joint pain or
`an increase in range of motion in knee joints,
`tenderness,
`by a reduction in walk-
`mcreased mobility as demonstrated
`in capacity to perform activities
`ing tame, and improvement
`of daily living impaired by the disease.
`of
`standard
`formulations
`trial comparing
`In a clinical
`naproxen 375 mg bid (750 mg a day) vs 750 mg bid (1500
`in the 750 mg group terminated prema-
`mg/day), 9 patients
`turely because of adverse events. Nineteen patients
`in the
`because of adverse
`1500 mg group terminated
`prematurely
`events. Most of these adverse events were gastrointestinal
`events.
`arthritis, os-
`In clinical studies in patients with rheumatoid
`has been
`arthritis,
`naproxen
`and juvenile
`teoarthritis
`in con-
`shown to be comparable to aspirin and indomethacin
`trolling the aforementioned measures of disease activity,
`the frequency and seventy of the milder gastrointesti-
`but
`and ner-
`nal adverse effects (nausea, dyspepsia, heartburn)
`lighthead-
`vous system adverse effects (tinnitus, dizziness,
`than in
`patients
`edness) were less in naproxen-treated
`those treated with aspirin or indomethacin.
`naproxen has been
`In patients with ankylosing
`spondyhtis,
`shown to decrease night pain, morning stiflhess and pam at
`the drug was shown to be as
`studies
`rest. In double-blind
`effective as aspirin, but with fewer side effects.
`a favorable
`response
`to
`acute gout,
`In patients with
`naproxen was shown by significant clearing of inflammatory
`(eg, decrease in swelhng, heat) withm 24 to 48
`changes
`hours, as well as by relief of pain and tenderness.
`Naproxen has been studied rp patients with mild to moder-
`orthopedic, postpartum
`ate pain secondary to postoperative,
`episiotomy anil uterine contraction pain and dysmenorrhea.
`tak-
`Onset of pain relief can begin within 1 hour in patients
`and within 30 minutes
`in patients
`talung
`ing naproxen
`naproxen sodium Analgesic effect was shown by such meas-
`increase in pain
`ures as reduction of pain intensity scores,
`ad-
`relief scores, decrease in numbers of patients
`reqmring
`and delay in time to remedi-
`ditional analgesic medication,
`cation. The analgesic effect has been found to last for up to
`12 hours.
`Naproxen may be used safely in combination with gold salts
`tria)s,
`in controlled clinical
`and/or corticosteroids;
`however,
`receiving corticoster-
`when added to the regimen of patients
`over
`to cause greater
`improvement
`oids, it did not appear
`alone. Whether naproxen has
`that seen with corticosteroids
`studied.
`eflect has not been adequately
`a "steroid-sparing"
`receiving gold salts,
`When added to the regimen of patients
`Its use in com-
`in greater improvement.
`naproxen did result
`because there
`is not recommended
`bmation with salicylates
`the rate of excretion of
`that aspirin increases
`is evidence
`that
`to demonstrate
`and data are inadequate
`naproxen
`over
`and aspirin produce greater
`improvement
`naproxen
`that achieved with aspirin alone. In addition, as with other
`frequency of
`the combination may result
`in higher
`NSAIDs,
`for either product alone.
`adverse events than demonstrated
`In 'Cr blood loss and gastroscopy studies with normal vol-
`as
`of 1000 mg of naproxen
`daily administration
`unteers,
`or 1100 mg of
`1000 mg of NAPROSYN (naproxen)
`ANAPROX (naproxen sodium) has been demonstrated
`to
`less gastnc bleeding and
`cause statistically
`significantly
`erosion than 3250 mg of aspirin.
`Three 6-week, double-bhnd, multicenter
`studies with
`(375 or 500 mg bid, n=385) and
`EC-NAPROSYN (naproxen)
`NAPROSYN (376 or 500 mg bid, n=279) were conducted
`including
`comparing EC-NAPROSYN with NAPROSYN,
`and osteoarthritis
`patients who
`arthritis
`355 rheumatoid
`had a recent history of NSAID-related GI symptoms. These
`indicated that EC-NAPROSYN and NAPROSYN
`studies
`in eScacy or safety and
`differences
`showed no sigiuficant
`Individual
`had similar prevalence of minor GI complaints.
`to
`preferable
`however, may find one formulation
`patients,
`the other.
`received
`patients
`fifty-three
`Five
`hundred
`and
`trials (mean
`EC-NAPROSYN during long-term open label
`length of treatment was 159 days) The rates for clinically-
`diagnosed peptic ulcers and GI bleeds were similar
`to what
`has been historically reported for long-term NSAID use.
`INDIVIDUALIZATION OF DOSAGE
`Suspension,
`NAPROSYN
`NAPROSYN,
`Although
`EC-NAPROSYN, ANAPROX and ANAPROX DS all circu-
`they have pharmacolunetic
`late in the plasma as naproxen,
`that may affect onset of action. Onset of pain re-
`differences
`in patients
`30 minutes
`taking
`lief can begin within
`taking
`in patients
`1 hour
`sodium and within
`naproxen
`in the smail
`naproxen. Because EC-NAPROSYN dissolves
`the absorption of the
`than in the stomach,
`rather
`intestine
`to the other naproxen formula-
`drug is delayed compared
`tions (see CLINICAL PHARMACOLOGY).
`is to
`for initiating
`therapy
`The recommended
`strategy
`and a startmg dose hkely to be efiec-
`choose a formulation
`the dosage based on ob-
`tive for the patient and then adjust
`servation of benefit
`events. A lower dose
`adverse
`and/or
`should be considered in patients with renal or hepatic im-
`(see PRECAUTIONS).
`pairment or in elderly patients
`
`C
`(pg/mL)
`T
`(hours)
`(pg-hr/mL)
`AUCo-izhr
`" Mean value (coeScient of variation)
`Be-
`am/ Tendonitisi
`Ane/gesia/Dysmenorrhea/Bursitis
`cause the sodium salt of naproxen is more rapidly absorbed,
`for the manage-
`ANAPROX/ANAPROX DS is recommended
`ment of acute painful conditions when prompt onset of pain
`starting dose is 550 mg
`relief is desired. The recommended
`followed by 550 mg every 12 hours or 275 mg every 6 to 8
`total daily dose should not
`hours, as required. The initial
`the total
`sodium. Therea(ter,
`exceed 1375 mg of naproxen
`daily dose should not exceed 1100 mg of naproxen sodium.
`of acute pain
`NAPROSYN may also be used for treatment
`EC-NAPROSYN is not recommended
`and dysmenorrhea,
`treatment of acute pain because absorption of
`for initial
`naproxen is delayed compared to other naproxen-containing
`(see CLINICAL PHARMACOLOGY and INDICA-
`products
`TIONS AND USAGE).
`starting dose is 750 mg of
`Acute Gout: The recommended
`the at-
`NAPROSYN followed by 250 mg every 8 hours until
`tack has subsided. ANAPROX may also be used at a start-
`ing dose of 825 mg followed by 275 mg every 8 hours as
`because of the
`needed EC-NAPROSYN is not recommended
`delay in absorption (see CLINICAL PHARMACOLOGY).
`Spondyii-
`Osreoarthritis/Rheumatoid
`Arthritis/Ankyiosing
`dose of naproxen is NAPROSYN or
`ris: The recommended
`NAPROSYN Suspension 250 mg, 375 mg or 500 mg taken
`twice daily (morning and evening) or EC-NAPROSYN 375
`mg or 500 mg taken twice daily. Naproxen sodium may also
`be used (see DOSAGE AND ADMINISTRATION).
`the dose of naproxen may
`During long-term administration
`response
`on the clinical
`be ad)usted up or down depending
`of the patient. A lower dady dose may suSce for long-term
`In patients who tolerate lower doses well,
`admiiustration.
`the dose may be increased to 1500 mg per day when a
`activity is re-
`level of anti-inflammatory/analgesic
`higher
`quired. When treating patients with naproxen 1500 mg/day
`the physician
`(as NAPROSYN or 1650 mg of ANAPROX),
`to offset
`should observe suScient
`increased clinical benefit
`increased risk. The morning
`and evening
`the potential
`of
`in size and administration
`doses do not have to be equal
`than twice daily does not gener-
`the drug more frequently
`(see CLINICAL PHAR-
`ally make a difFerence
`in response
`MACOLOGY).
`The use of NAPROSYN Suspension al-
`Juvenile Arthritis:
`In pediatric patients,
`lows for more ileiuble dose titration.
`levels of naproxen
`doses of 5 mg/kg/day
`produced plasma
`taking 500 mg of naproxen
`to those seen in adults
`similar
`(see CLINICAL PHARMACOLOGY).
`10
`total daily dose is approximately
`The recommended
`mg/kg given in two divided doses (ie, 5 mg/kg given twice a
`day) (see DOSAGE AND ADMINISTRATION).
`INDICATIONS AND USAGE
`as NAPROSYN, EC-NAPROSYN, ANAPROX,
`Naproxen
`ANAPROX DS or NAPROSYN Suspension are indicated for
`arthritis, osteoarthritis,
`anky-
`the treatment of rheumatoid
`and juveiule arthritis.
`losing spondylitis
`as NAPROSYN Suspension is recommended
`for
`Naproxen
`to obtain the maxi-
`arthritis
`in order
`juvenile rheumatoid
`mum dosage flexibility based on the patient's weight
`Naproxen as NAPROSYN, ANAPROX, ANAPROX, DS and
`are also indicated for the treat-
`NAPROSYN Suspension
`ment of tendinitis, bursitis, acute gout, and for the manage-
`EC-NAPROSYN
`ment of pain and primary dysmenorrhea.
`of acute pain be-
`treatment
`for initial
`is not recommended
`cause the absorption of naproxen is delayed compared to ab-
`(see
`products
`from other naproxen-containing
`sorption
`CLINICAL PHARMACOLOGY and DOSAGE AND AD-
`MINISTRATION).
`CONTRAINDICATIONS
`in patients who
`All naproxen products are contraindicated
`have had allergic reactions to prescription as well as to over-
`It is also contra-
`the-counter products containing naproxen
`in whom aspirin or other nonsteroidal
`indicated in patients
`induce the syndrome of
`anti-inflammatory/analgesic
`drugs
`and nasal polyps. Both types of reactions
`rhinitis
`asthma,
`have the potential of being fatal Anaphylactoid
`reactions to
`naproxen, whether of the true allertnc type or the pharmo-
`syndrome)
`(eg, aspirin hypersensitivity
`cologic idiosyncratic
`type, usually but not always occur in patients with a known
`of
`history of such reactions. Therefore, careful questioning
`for such things as asthma, nasal polyps, urticaria
`patients
`anti-inflam-
`associated with nonsteroidal
`and hypotension
`In addi-
`matory drugs before starting therapy is important.
`treatment
`if such symptoms
`occur during therapy,
`tion,
`should bo discontinued.
`WARNINGS
`Risk of Gi U/ceration, Biseding and Perforation with IIISA/0
`toxicity such as bleed-
`Serious gastrointestinal
`Therapy:
`ing, ulceration and perforation can occur at any time, with
`treated chroni-
`in patients
`or without warning
`symptoms,
`cally with NSAID therapy. Although minor upper gastroin-
`are common
`usually
`such as dyspepsia,
`testinal problems
`should remain alert
`developing early in therapy, physicians
`treated chronically
`for ulceration and bleeding in patients
`with NSAIDs even in the absence of previous GI tract symp-
`trtals of several
`observed m clmical
`In patients
`toms.
`upper GI ulcers,
`to 2 yruirs'uration,
`symptomatic
`months
`
`PHYSICIANS'ESK REFERENCE
`
`EC.NAPROSYN*
`500 mg bid
`
`94.9 (18%)
`4 (39%)
`845 (20%)
`
`NAPROSYN*
`500 mg bid
`
`97.4 (13%)
`1.9(61%)
`767 (15%)
`
`to occur in approxi-
`gross bleeding or perforation
`appear
`mately 1% of patients treated for 3 to 6 months and in about
`2% to 4% of patients
`treated for 1 year.
`the signs and/or
`about
`should inform patients
`Physicians
`symptoms of serious GI toxicity and what steps to take if
`they occur.
`Studies to date with all naproxen products have not identi-
`fied any subset of patients not at risk of developing
`peptic
`ulceration and bleeding or any differences between different
`in their propensity to cause peptic ulcer-
`naproxen products
`ation and bleeding. Except for a prior history of serious GI
`events and other risk factors known to be associated with
`smoking, etc., no
`such as alcoholism,
`peptic ulcer disease,
`risk factors (eg, age, sex) have been associated with in-
`creased risk. Elderly or debilitated patients seem to tolerate
`and
`than other individuals
`ulceration or bleeding less well
`reports of fatal GI events are in this pop-
`most spontaneous
`concerning the rel-
`ulation Studies to date are inconclusive
`ative risk of various NSAIDs in causing such reactions.
`High doses of any NSAID probably carry a greater nsk of
`trials showmg
`controlled clinical
`these reactions, although
`this do not exist in most cases. In considering the use of rel-
`dosage range),
`atively large doses (within the recommended
`to offset the poten-
`should be anticipated
`suScient benefit
`tial increased risk of GI toxicity.
`PRECAUTIONS
`PRODUCTS SUCH
`NAPROXEN-CONTAINING
`Genera/:
`AS NAPROSYN, EC.NAPROSYN, ANAPROX, ANAPROX DS,
`AND OTHER
`SUSPENSION, ALEVEv,
`NAPROSYN
`NAPROXEN PRODUCTS SHOULD NOT BE USED CONCOM-
`ITANTLY SINCE THEY ALL CIRCULATE IN THE PLASMA AS
`THE NAPROXEN ANION.
`If the steroid dose is reduced or eliminated during therapy,
`the steroid dosage should be reduced slowly and the pa-
`tients should be observed closely for any evidence of adverse
`and exacerbation of
`insuificiency
`adrenal
`including
`eflects,
`symptoms of arthritis.
`values of 10 grams or less
`Patients with initial hemoglobin
`who are to receive long-term therapy should have hemoglo-
`bin values determmed
`periodically.
`activities of the drug
`and anti-inflammatory
`The antipyretic
`their
`thus diminishing
`may reduce fever and inflammation,
`utility as diagnostic signs in detecting complications of pre-
`conditions.
`painful
`noninflammatory
`sumed noninfectious,
`studies with
`in animal
`Because of adverse
`eye findings
`stud-
`that ophthalmic
`drugs of this class, it is recommended
`in vision oc-
`ies be carried out if any change or disturbance
`curs.
`anti-inflamma-
`Rene/ Effects: As with other nonsteroidal
`to ani-
`of naproxen
`long-term administration
`tory drugs,
`mals has resulted m renal papillary necrosis and other ab-
`there have been reports
`In humans,
`renal pathology.
`normal
`and
`proteinuria
`hematuna,
`of acute interstitial
`nephritis,
`associated with naproxen-
`occasionally nephrotic
`syndrome
`containing products and other NSAIDs since they have been
`marketed.
`toxicity has been seen in patients
`A second form of renal
`anti-inflam-
`taking naproxen as well as other nonsteroidal
`leading
`conditions
`In patients with prerenal
`matory drugs.
`to a reduction in renal blood flow or blood volume, where the
`role in the mamte-
`have a supportive
`renal prostaglandins
`of a nonsteroidal
`administration
`nance of renal perfusion,
`reduc-
`drug may cause a dose-dependent
`anti-inflammatory
`formation and precipitate overt renal
`tion in prostaglandin
`risk of this reaction
`Patients at greatest
`decompensation
`failure,
`function, heart
`liver
`are those with impaired renal
`those taking diuretics and the elderly. Discon-
`dysfunction,
`therapy is typ-
`anti-inflammatory
`tinuation of nonsteroidal
`state.
`ically followed by recovery to the pretreatment
`are eliminated
`primaxdy
`by
`and its metabolites
`Naproxen
`the drug should be used with caution
`therefore,
`the kidneys;
`and
`function,
`impaired renal
`in patients with significantly
`and/or creatinine clear-
`the monitoring of serum creatinine
`ance is advised in these patients Caution should be used if
`clearance of
`the drug is given to patients with creatinine
`because accumulation of naproxen
`less than 20 mL/minute
`metabolites has been seen in such patients.
`Chronic alcoholic liver disease and probably other diseases
`re-
`(albumin)
`plasma proteins
`with decreased or abnormal
`the
`but
`of naproxen,
`duce the total plasma
`concentration
`is increased.
`of unbound
`naproxen
`concentration
`plasma
`Caution is