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`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 2
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`

`

`CLINICAL THERAPEUTICS®/VOL. 16, NO. 6, 1994
`
`Steady-State Pharmacokinetics of Enteric-Coated Naproxen
`Tablets Compared with Standard Naproxen Tablets
`
`Donald Jung, PhD, and Kenneth E. Schwartz, MD
`Syntex Research, Palo Alto, California
`
`ABSTRACT
`
`In thi s open-label, randomized, cross(cid:173)
`over study, 24 healthy volunteers (12
`men and 12 women) received either en(cid:173)
`teric-coated (EC) naproxen tablets 500
`mg twi ce daily or standard naproxen
`tablets 500 mg twice daily for 7 days.
`In each of the two study periods, blood
`sampling began on day 8, after one last
`dose of the study dru g was admini s(cid:173)
`tered, to determine and compare steady(cid:173)
`state pharmacokinetics for each of the
`two naproxen formulations. The plasma
`half-life of naproxen averaged 16.3 and
`16. 9 hours following EC naproxen and
`standard naproxen treatments, respec(cid:173)
`tively. Mean time to maximum plasma
`concentration (T max) was greater for EC
`naproxen than for stand ard naproxen
`(4.0 vs 1.9 hours), while the maximum
`observed plasma concentration (Cmax)
`was sli ghtly, but not signifi ca ntl y,
`small er (94.9 vs 97.4 µ g/mL, respec(cid:173)
`tively). The mean values for average
`
`plasma concentration (Cave) and mini(cid:173)
`mum pla sma concentration for EC
`naproxen were 70.4 and 60.6 µg/mL,
`respectively, compared with 63.9 and
`44.1 µ g/mL for standard naproxen.
`The mean plasma fluctuation about the
`mean was greater
`for
`standard
`naproxen than for EC naproxen (85.3 %
`vs 49.3%), while the mean area under
`the plasma concentration-time curve
`(AUC) was smaller for standard
`naproxen (766.8 vs 845.0 µg x h/mL).
`At steady state, EC naproxen was sim(cid:173)
`ilar to standard naproxen tablets with
`respect to Cmax, Cave, Cma,:Cave, 0- to 12-
`hour AUC, and half- life but differed in
`T max-
`In additi on, flu ctuations about
`Cave in pl asma levels were considerably
`lower with EC naproxe n than with
`standard naproxen.
`
`INTRODUCTION
`
`Naproxen is a nonsteroidal anti-inflam(cid:173)
`matory drug with analgesic and antipy-
`
`0149-291 W4IS3.S0
`
`923
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`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 3
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`

`

`retie properties. The e fficacy and tol(cid:173)
`e rability of naproxen in the ma nage(cid:173)
`me nt o f rheumatoid di sease s, go ut,
`pain, and dysmenorrhea have been well
`establi shed in ma ny years of c linical
`use. 1 An enteric-coated (EC) formula(cid:173)
`tion' of naproxen was developed to re(cid:173)
`lease na proxe n at the pH level of the
`small intestine , where di ssolution takes
`place.
`An in vivo eva lu ati o n o f EC na(cid:173)
`proxe n tabl e ts ha s s how n th a t the
`naproxen blood levels over time were
`consistent with th e delayed re lease of
`naproxen from the tabl ets,2 but no data
`comparin g the steady-state pharmaco(cid:173)
`kinetics of EC naproxen with standard
`na proxen ha ve been publi she d. The
`current study was designed to compare
`the stead y-state pharmacokin eti cs of
`EC naproxen and standard tabletst in a
`group of healthy men and women.
`
`SUBJECTS AND METHODS
`
`Thi s was an o pe n-labe l, rando mi zed
`stud y o f c rossover des ig n. Twe nty(cid:173)
`four heal thy men and women w hose
`body weights were within 15% of the
`average weig ht for th e ir age and
`height, as determined from the Metro(cid:173)
`politan Life Insurance tables, partici(cid:173)
`pated in the study. 3 Participants were
`selected on the basis of an essentially
`problem-free medical history, a normal
`phy s ica l e xamina tion , and a ro utine
`laboratory test profile showing no clin(cid:173)
`ically sig nificant abnormalities. Ins ti(cid:173)
`tutio nal review board approval was ob(cid:173)
`ta in ed . The study was ex pla ined to
`
`Trademarks: EC-Naprosyn®' and Naprosyn®t (Syn(cid:173)
`tex Laboratories, Inc., Palo Alto, California).
`
`924
`
`CLlN ICAL THERAPEUTICS®
`
`subjects in no ntechnical terms, and all
`subjects signed a written informed con(cid:173)
`sent form and an Experimental Subjects
`Bill of Rights before participating.
`The two study regimens were: 500-
`mg EC naproxen tablets twice daily fo r
`7 days plus one dose o n day 8, and 500-
`mg standard naproxen tablets twice daily
`for 7 days plus one dose on day 8.
`After an overnig ht fast (beginning at
`9:30 PM the prev ious night), each sub(cid:173)
`ject received, in random order, 500 mg
`twice daily EC na proxe n or sta ndard
`naproxen for 7 days and a fin al dose on
`day 8. Adverse e vents were mo nitored
`at each blood d rawing, and the subjects
`informed the study physician or trained
`o bserver of any ad verse events that oc(cid:173)
`curred during the study. A washout pe(cid:173)
`riod of 8 days fo llowed each treatme nt.
`Se ri al bl ood samples we re collected
`afte r the fin al morning dose for up to
`72 ho urs. To det ermin e naprox e n
`tro ug h leve ls, s ing le blood sa mple s
`were also collecte d on days 6 and 7 be(cid:173)
`fore the morning dose. The plasma from
`each bl ood sample was separated i m(cid:173)
`medi ate ly, tra nsferred into vials, and
`frozen for subsequent assay of naprox(cid:173)
`e n by usin g hig h-performance liquid
`chromatog raphy.4 Plasma levels below
`the qua nti fi catio n lim it of 0.5 µ g/mL
`naproxen at time zero were set to zero
`for the calculation of mean plas ma lev(cid:173)
`els and computed variables.
`
`StaJistical and Pharmacokinetic Analyses
`
`The foll owing pharmacokinetic vari(cid:173)
`ables were determined on day 8:
`•T max-time to maxi mu m p las ma
`concentratio n;
`•Pl as ma ha lf- life- computed over
`the 24- to 72-hour interval by using log
`
`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 4
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`

`

`D. JUNG AND K.E. SCHWARTZ
`
`Table I. Demographic characteristics.
`
`Variable
`
`Age (y)
`Mean±SD
`Range
`Body weight (kg)
`Mean±SD
`Range
`Height (cm)
`Mean±SD
`Range
`
`Men (n = 12)
`
`Women (n = 12)
`
`29.8± 4.6
`22- 35
`
`82± II
`64-94
`
`184±6
`175- 193
`
`30.9 ±7. 1
`22-47
`
`64±6
`55- 75
`
`168±6
`157-1 76
`
`linear regression analysis of the plasma
`concentration versus time data;
`•Cmax- maxi mum observed pl asma
`concentration;
`•0- to 12-hour AUC-area under the
`plasma concentration-time curve from
`0 to 12 hours, computed using the lin(cid:173)
`ear trapezoidal rule;
`•Cave-average plasma concentration
`computed as the ratio of AUC divided
`by the dosing interval (12 hours);
`•C1ow-minimum (trough ) pl asma
`concentration at time of dosing com(cid:173)
`puted as the mean of the zero and 24-
`hour values ;
`•Cma, :C1ow- peak to trough plas ma
`ratio;
`•Cma, :Cave-peak to average plasma
`concentration ratio;
`•Fluctuation-100 x (Cmax - Cmin)/
`Cave ( ie, percent fluctuation about aver(cid:173)
`age plasma concentration).
`An analysis of variance (AN OVA)
`model appropri ate for a crossover de(cid:173)
`sign was used, 5 and the statistical anal(cid:173)
`yses were performed for the pharmaco(cid:173)
`kineti c variables according to the
`General Linear Mode l procedure of the
`Statistical Analysis System, Version
`5.16. 6 The ANOVA model in c luded
`
`terms for sequence, subjects within se(cid:173)
`quence, formulation, and period effects.
`Ninety percent c lassic confidence in(cid:173)
`tervals7 for the ratio of EC naproxen to
`standard naproxen were obtained using
`the t distribution. Confidence limits
`(90%) on the difference in the regime n
`means were computed using an error
`term derived from ANOVA. These lim(cid:173)
`its were then expressed as percentages
`of the re ference mean by di viding the
`upper and lower limits of the confi(cid:173)
`dence inte rval by the estimated refer(cid:173)
`ence mean and then adding 100%. Two
`reg imens were considered equi vale nt
`with respect to a given variable if the
`two means differed by less than 20% or
`the confidence interval was within 80%
`to 120%, with 90% confidence.
`In addition, the trough levels on days
`6, 7, and 8 were compared to demon(cid:173)
`strate that steady-state levels had bee n
`attained by day 8. ANOVA procedures
`with terms in the model for subject and
`day were used for this comparison.
`
`RESULTS
`
`The demographic characteristics (Table
`I) were calculated separately for the 12
`
`925
`
`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 5
`
`

`

`men and 12 women in the study. All
`subjects completed the study normally.
`Adverse events were reported by 9
`(37.5%) of 24 subjects. Headaches and
`gastrointestinal complaints were the
`most frequently reported adverse events.
`With the standard naproxen tablet regi(cid:173)
`men, headaches and stomachaches oc(cid:173)
`curred in three subjects and dyspepsia
`in one. With the EC naproxen regimen,
`headaches occurred in three subjects,
`but there were no gastrointestinal com(cid:173)
`plaints. Most events associated with
`the two naproxen regimens were classi(cid:173)
`fied by the investigator as probably not
`related to the study medication , and
`none were clinically serious. Concom(cid:173)
`itant medications take n during the
`study were not considered like ly to
`affect the conduct or outcome of the
`
`CLINICAL THERAPEUTICS®
`
`study. Laboratory tests and physical
`examinations revealed no c lini call y
`significant abnormalities.
`Stati stically s ignificant (P < 0 .05)
`diffe re nces in trough concentrations
`between day s were observed for the
`naproxen standard tablets; there were
`no statistically significant time (day)
`effects for th e EC naprox e n table ts
`(Table II). The mean trough levels for
`the standard naproxen tablet were 46.0,
`49.9, and 45.9 µg/mL for days 6, 7, and
`8, respectively. The significant differ(cid:173)
`ence was owing to a higher naproxen
`concentration on day 7 than that o n
`days 6 and 8. The ratios and confi(cid:173)
`dence limits (90%) were calculated for
`the ratios of days 6 and 7 to day 8 for
`each formulation and are shown in
`Table II. Although significant day ef-
`
`Table IT. Naproxen trough plasma concentrations (µg/mL) and steady-state comparisons.
`
`p•
`
`0.244
`
`0.020
`
`Day6
`
`Day7
`
`Day8
`
`Day6:8
`
`Day7:8
`
`Ratio
`
`ECNaproxen
`Mean
`SD
`Cvar
`Minimum
`Maximum
`Ratio(%)
`cit
`Standard Naproxen
`Mean
`SD
`Cvar
`Minimum
`Maximum
`Ratio(%)
`cit
`
`73.4
`18.8
`25.7
`46.1
`120.4
`
`46.0
`9.0
`19.5
`27.8
`64.1
`
`76.8
`23.3
`30.4
`20.7
`123.1
`
`49.9
`11.9
`23.8
`26.7
`77.6
`
`68.5
`2 1.1
`30.8
`29.0
`115.2
`
`45.9
`9.4
`20.6
`26.6
`65.4
`
`107
`95-11 9
`
`11 2
`100-124
`
`100
`95-106
`
`109
`103- 114
`
`EC= enteric-<:oated; Cvar = coefficient of variation; CI= confidence interval.
`• P value is for day effect (analysis of variance model has terms for subject and day).
`t90% Cl (limits in %).
`
`926
`
`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 6
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`

`

`D. JUNG AND K.E. SCHWARTZ
`
`- 80
`..J 1 :::t - 60
`l!! -C
`
`40
`
`20
`
`C
`0
`:;:.
`
`~
`C
`0
`0
`
`0
`
`2
`
`4
`
`6
`
`8
`10
`Time (h)
`
`12 24
`
`48 72
`
`Figure 1. Mean naproxen plasma concentrations at steady state (day 8) over time following
`oral administration of standard naproxen <•) and enteric-coated (EC) naproxen (e ).
`fec ts were observed for the standard
`compared with 63.9 and 44.1 µ g/mL
`tablet, steady state appears to have
`for standard naproxen. The mean
`been reached by day 6.
`plasma fluctuation about the mean was
`The mean plasma profiles of naproxen
`greater for standard naproxen than for
`at steady state (day 8) after oral adminis(cid:173)
`EC naproxen (85.3% vs 49.3 %), while
`tration of standard naproxen and EC
`the mean AUC was smaller (766.8 vs
`naproxen in the fasting state are plotted
`845.0 µ g x h/mL).
`in Figure 1. Figure 2 compares the two
`Table III also shows the ratios of the
`formu lations with respect to 12-hour
`various mean computed variables (EC
`AUCs for each subject.
`naproxen:standard naproxen) and the
`Table III summarizes the computed
`90% confidence intervals for the differ(cid:173)
`variab les at steady-state levels (day
`ence in means, expressed as percent(cid:173)
`8). The plasma half-life averaged
`ages. Based on the 80%: 120% rule for
`16.3 hours after EC naproxen admin(cid:173)
`bioequivalence, EC naproxen was
`istration and 16. 9 hours after standard
`bioequivalent to stan dard naproxen
`naproxen. Mean T max was greater for
`with re spect to half-life , Cmax, Cave,
`EC naproxen than standard naproxen
`Cmax:Cave, and 0- to 12-hour AUC. The
`(4.0 vs 1.9 hours), while Cmax was
`limits for the other computed pharma(cid:173)
`slightly but not significantly s maller
`cokinetic parameters (T max, C1ow, Cmax:
`(94.9 vs 97.4 µg/mL, respectively).
`C1ow, and percent fluctuation) were
`The mean Cave and C.ow for EC na(cid:173)
`not contained within the 80% to 120%
`proxe n were 70.4 and 60.6 µg/mL ,
`interval.
`
`927
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`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 7
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