DRUG DISPOSITION
`
`Clin. Pharmacokinet, 1997 Apr: 32 (4): 268-293
`0312-5963/97/OC()<H1268/S13.cxJ/O
`
`© Adis International Limited. All rights reserved.
`
`Clinical Pharmacokinetics of Naproxen
`
`Neal M. Daviesl and Keith E. Anderson2
`1 Faculty of Medicine, Department of Pharmacology and Therapeutics,
`University of Calgary, Calgary, Alberta, Canada
`2 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton,
`Alberta, Canada
`
`Contents
`.......... .
`Summary
`1. Pharmacokinetic Properties
`1 . 1 Absorption.
`1.2 Distribution.
`1.3 Metabolism
`1.4 Elimination .
`2. Therapeutic Implications for Naproxen
`2.1 Dose and Therapeutic Range ...
`2.2 Disease and Naproxen Pharmacokinetics
`2.3 The Influence of Age on Naproxen Pharmacokinetics
`3. Drug Interactions . . . . . . . . . . . .
`. ..... .
`3.1 Effect of Other Drugs on the Pharmacokinetics of Naproxen
`3.2 Effect of Naproxen on the Pharmacokinetics of Other Drugs
`4. Conclusions . . . . .
`. . . . . . . . . . . . . . . . . . . . . . .
`
`268
`269
`269
`274
`278
`279
`280
`280
`281
`285
`286
`286
`288
`289
`
`Summary
`
`Naproxen is a stereochemically pure nonsteroidal anti-inflammatory drug of
`the 2-arylpropionic acid class. The absorption of naproxen is rapid and complete
`when given orally. Naproxen binds extensively, in a concentration-dependent
`manner, to plasma albumin. The area under the plasma concentration-time curve
`(AUC) of naproxen is linearly proportional to the dose for oral doses up to a total
`dose of 500mg. At doses greater than 500mg there is an increase in the unbound
`fraction of drug, leading to an increased renal clearance of total naproxen while
`unbound renal clearance remains unchanged.
`Substantial concentrations of the drug are attained in synovial fluid, which is
`a proposed site of action for nonsteroidal anti-inflammatory drugs. Relationships
`between the total and unbound plasma concentration, unbound synovial fluid
`concentration and therapeutic effect have been established.
`Naproxen is eliminated following biotransformation to glucuroconjugated and
`sulphate metabolites which are excreted in urine, with only a small amount of the
`drug being eliminated unchanged. The excretion of the 6-0-desmethylnaproxen
`metabolite conjugate may be tied to renal function, as accumulation occurs in
`end-stage renal disease but does not appear to be influenced by age.
`Hepatic disease and rheumatoid arthritis can also significantly alter the dis(cid:173)
`position kinetics of naproxen. Although naproxen is excreted into breast milk,
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 1
`
`

`

`Naproxen
`
`269
`
`the amount of drug transferred comprises only a small fraction of the maternal
`exposure.
`Significant drug interactions have been demonstrated for probenecid, lithium
`and methotrexate.
`
`Naproxen [S-( +)-2-(6-methoxynaphth-2-yl)pro(cid:173)
`pionic acid] is a 2-arylpropionic acid (2-APA)
`nonsteroidal anti-inflammatory drug (NSAID).
`Naproxen is a potent inhibitor of prostaglandin
`synthesis,[I] and is now marketed as an over-the(cid:173)
`counter medication in the US. Naproxen is prescribed
`for the treatment of rheumatoid arthritis, osteoar(cid:173)
`thritis, ankylosing spondylitis, and acute gouty ar(cid:173)
`thritis. Therapeutic doses of naproxen have proven
`to be equi-efficacious when compared with other
`commonly used NSAIDsP-4] Naproxen also has anti(cid:173)
`pyretic activity and is effective in the treatment of
`dysmennorhoea.l4] Naproxen exhibits analgesic ef(cid:173)
`fects and is used clinically for short term allevia(cid:173)
`tion of post-operative pain, as well as migraine at(cid:173)
`tacks.[5] Gastrointestinal complications are the most
`common adverse effect, although renal dysfunc(cid:173)
`tion and hypersensitivity reactions also occur.[4]
`The clinical pharmacokinetics and pharmaco(cid:173)
`dynamics of several of the chiral NSAIDs have
`been well established. [6-111 However, as each mem(cid:173)
`ber of this pharmacological class demonstrates
`unique pharmacokinetic features which distinguish
`them from each other, assessment of the pharma(cid:173)
`cokinetics of each NSAID, on an individual basis,
`is essential.
`General review articles are available dealing with
`the pharmacological properties and therapeutic
`utility of naproxenP-4] However, these articles do
`not give detailed information on the unique features
`ascribed to the clinical pharmacokinetics of napro(cid:173)
`xen. This article comprehensively reviews the clin(cid:173)
`ical pharmacokinetics of naproxen and its metabo(cid:173)
`lites.
`
`1. Pharmacokinetic Properties
`
`1 .1 Absorption
`
`Naproxen is usually administered orally, but has
`also been administered topically, intravenously,
`
`intramuscularly and rectally. Conventional regular
`release tablets, capsules, enteric-coated tablets,
`suspensions, sustained and controlled-release pre(cid:173)
`parations, gels and suppositories are commercially
`available.
`Table I shows the absorption properties of
`naproxen when administered in different formula(cid:173)
`tions in various disease states. Naproxen appears
`to be completely absorbed, whether given as a sus(cid:173)
`pension, capsule or tablet.[63] Following oral ad(cid:173)
`ministration, the extent of naproxen absorption re(cid:173)
`sults in a similar area under the concentration-time
`curve (AUC) compared with intravenous adminis(cid:173)
`tration.[63,64] Following single dose administration
`of regular release preparations, doses of up to 4g
`are rapidly absorbed, with peak plasma or serum
`drug concentrations (Cmax) observed between O.S
`and 3 hours after administration.l 15,23,64]
`The AUC is linearly proportional to dose up to
`a total dose of SOOmg.l64] Multiple dose administr(cid:173)
`ation yields absorption characteristics similar to
`those seen after single doses. [571
`Naproxen is a weak acid (pKa = 4.1S). Attempts
`have been made, based on this physicochemical
`characteristic, to enhance the rate of absorption
`from different naproxen formulations and thereby
`provide an earlier onset of pharmacological ef(cid:173)
`fect. The sodium salt tablets have been shown to be
`absorbed at a higher rate with higher plasma con(cid:173)
`centrations when compared to naproxen free acid
`tablets in healthy volunteers.l65] However, this
`pharmacokinetic feature did not result in an earlier
`onset of analgesia. In fact, statistically significant
`differences in analgesic effects were not seen until
`4 or S hours after medication in patients with post(cid:173)
`partum pain.[65]
`
`1. 1. 1 Routes of Administration
`When compared with the bioequivalent formula(cid:173)
`tions of regular release tablets, enteric-coated, sus(cid:173)
`tained release and controlled-release preparations have
`
`© Adis International Limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Apr; 32 (4)
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 2
`
`

`

`270
`
`Davies & Anderson
`
`Table I. Absorption characteristics of naproxen (single doses of oral formulations administered to healthy adults except where indicated)
`
`No. of patients
`(type)
`6
`
`Agea (y)
`[range]
`NR
`
`9 RD children
`6
`
`16
`
`12
`
`12
`
`10.8 [5-14]
`23 [22-25]
`
`20 [18·23]
`
`NR
`
`NR
`
`NR
`
`26.6 [23-43]
`63.8 [54·74]
`61.25 [50-71]
`34 [24-45]
`8
`8 MRF
`56 [34·79]
`56 [42-67]
`8 SRF
`11 hepatic disorders NR
`57 [34-77]
`9 NH
`11
`28 [21-39]
`
`3 febrile children
`7 post-op children
`12
`
`12
`
`8
`
`10
`
`11
`
`11
`
`11
`
`6
`
`[6-13]
`
`[23-42]
`
`[23-42]
`
`28
`
`[20-52]
`
`[19-25]
`
`[21-51]
`
`[19-25]
`
`[20-54]
`
`Dose
`(no. of days)
`(3 x 100mg)
`150mg CW supp
`300mg CW supp
`150mg WS supp
`300mg WS supp
`5 mg/kg, <50kg and 250mg >50kg
`500mg
`500mg supp
`1000mg
`2000mg
`3000mg
`4000mg
`Sequence 1
`250mg bid x 7 D
`250mg bid & PB 500mg bid x 7 D
`Sequence 2
`250mg bid x 7 D
`250mg bid & PB 500mg bid x 7 D
`250mg
`250mg
`250mg
`250mg
`250mg
`250mg
`250mg
`250mg
`250mg
`250mg + AIOH, 200 mg/ml; MgOH, 200
`mg/5ml; and SIM, 20 mg/5ml
`10 mg/kg suspension
`10 mg/kg suspension
`250mg 1st time
`250mg 2nd time
`250mg 1 st time
`250mg 1 st time
`250mg
`250mg + 4g CSM in 100ml orange juice
`500mg EC
`500mg
`500mg EC x5 D
`250mg bid x 5 D
`500mg EC bid x 5D
`500mg bid x 5 D
`500mg sodium supp
`500mg tablets
`500mg sodium supp
`500mg supp
`
`Cmax
`(mg/L)
`-57
`-42
`-23
`-48
`-32
`59.4
`77.6
`65.7
`110
`155
`169
`210
`
`55.5
`67.7
`
`64.5
`43.5
`52.63
`49.8
`40.85
`44.3
`31.5
`27.0
`44.69
`18.89
`34.8
`37.2
`
`55
`49
`54.8
`65.1
`53
`62.8
`52.63
`34.49
`53.4
`77.2
`66.2
`74.9
`113.5
`106.3
`65.8
`73.4
`78.8
`59.6
`
`tmax
`(h)
`-2
`-4
`-4
`-2
`-2
`1-3
`2
`2
`NR
`NR
`NR
`NR
`
`NR
`NR
`
`NR
`NR
`1.78
`2.5
`1.05
`2
`2
`2
`2.59
`5
`2.6
`2.5
`
`NR
`NR
`2.9
`1.7
`3.1
`1.8
`2
`4.11
`5.6
`1.8
`4.5
`1.4
`4.7
`1.4
`1.4
`2.4
`0.9
`2.7
`
`AUC
`(mg/L· h)
`653
`345
`641
`393
`633
`774
`NR
`NR
`1402
`2187
`2614
`2796
`
`1155
`1926
`
`1604
`821
`269.96
`241.742
`187.05
`797
`763
`475
`NR
`566.73
`580
`579
`
`821
`713
`992
`1094
`858
`977
`NR
`631
`1494
`1324
`1156
`1248
`984
`861
`1456
`1435
`1675
`1448
`
`Reference
`
`12
`
`13
`14
`
`15
`
`16
`
`16
`
`17
`
`18
`
`19
`20
`21
`
`22
`
`23
`
`24
`
`25
`
`25
`
`25
`
`25
`
`26
`
`26
`
`© Adis International Limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Apr; 32 (4)
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 3
`
`

`

`Naproxen
`
`Table I. Contd
`
`No. of patients
`(type)
`10
`
`10 E
`
`10
`
`Agea (y)
`[rangeJ
`[22-39J
`
`[66-81J
`
`29.1 [22-39J
`
`10AC
`
`41.1 [31-59J
`
`7
`
`23 [19-28J
`
`13EOA
`6 Middle aged OA
`1 RA
`
`84.2 [76-93J
`53.9 [49-64J
`58
`
`6
`
`12
`
`5
`6
`
`14
`
`12
`
`14
`
`8 RA
`8
`12
`
`14
`
`60A
`23
`
`25 E
`
`7
`10 RA
`22
`12
`
`24.3 [21-30J
`
`[18-27J
`
`[22-30J
`[21-30J
`
`[22-30J
`
`[22-30J
`
`[22-30J
`
`62 [55-65J
`24 [21-27J
`32.8
`
`26.5 [21-35J
`
`[63-75J
`[19-32J
`
`[65-74J
`
`median 33 [26-36J
`median 69 [66-85J
`34.3 [21-44J
`[25-42J
`
`Dose
`(no. of days)
`375mg
`375mg x 9 days
`375mg
`375mg x 9 days
`375mg
`375mg bid x 13 doses
`375mg
`375mg bid x 13 doses
`1000mg qd x 4 days
`500mg bid x 4 days
`500mg bid x 21 days
`500mg bid x 21 days
`500mg bid active disease
`500mg bid improvement
`500mg 500 mg + sucralfate 2g
`
`500mg
`500mg + sucralfate 2g
`500mg bid for 10 doses
`500mg bid for 10 doses sucralfate
`
`500mg vaginal supp
`750mg CR
`750mg
`1000mg CR
`500mg bid
`750mg CR x 5 days
`375mg bid x 5 days
`100mg CR x 7 days
`500mg bid x 7 days
`500mg bid
`500mg bid
`500mg
`500mg + SGT 200mg
`500mg bid
`1000mg CR
`500mg bid x 7 D
`1000mg CR qd x 7 D
`500mg bid
`375mg bid x 15 doses
`750mg bid x 15 doses
`375mg bid x 15 doses
`750mg bid x 15 doses
`1000mg
`1000mg
`500mg supp
`1000mg CR fasting
`1000mg CR postprandial
`
`Cmax
`(mg/L)
`61.5
`58.2
`59.5
`64.2
`63.2
`94.8
`47.4
`84.2
`NR
`NR
`NR
`NR
`90.9
`125.6
`95.6
`84.2
`82.7
`76.0
`
`108.5
`99.3
`8.1
`47.9
`93.2
`58.5
`81.2
`70.1
`90.4
`78.3
`101.7
`79
`110
`63.3
`60.4
`81.3
`58.4
`97.2
`72.4
`60.7
`79.9
`110.9
`71.6
`109.7
`107.3
`111.5
`54.5
`63.1
`86.1
`
`tmax
`(h)
`1.86
`1.46
`2.22
`1.84
`1.4
`1.5
`1.3
`1.8
`NR
`NR
`NR
`NR
`NR
`NR
`2.2
`4.1
`1.4
`2.2
`
`1.8
`2.3
`6-8
`6.0
`1.7
`10.2
`2.0
`4.5
`1.7
`5.0
`1.4
`NR
`NR
`0.95
`1.10
`1.4
`11.3
`1.5
`3.4
`0.8
`[2-4J
`[2-4J
`[2-4J
`[2-4J
`1
`2
`3.1
`9.67
`7.67
`
`AUC
`(mg/L· h)
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`1650
`2780
`487
`369
`699
`1134
`1624
`1609
`1310.4
`1288.8
`
`1761.0
`1666.2
`NR
`1551
`1435
`1920
`2036
`1293
`1416
`1319
`1480
`641
`896
`685
`651
`1907.3
`1703.2
`1397.9
`1286.2
`NR
`696
`961
`670
`977
`2171
`2073
`1151
`2221
`2111
`
`271
`
`Reference
`
`27
`
`28
`
`29
`
`30
`
`31
`
`32
`
`33
`
`34
`35
`
`35
`
`35
`
`35
`
`36
`
`37
`
`38
`
`39
`40
`
`41
`
`42
`43
`
`© Adis International Limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Apr; 32 (4)
`
`Continued over page
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 4
`
`

`

`272
`
`Davies & Anderson
`
`Table I. Contd
`
`No. of patients
`(type)
`12
`
`Age" (y)
`[range]
`21.6 [18-32]
`
`6 RA
`
`58.8 [49-64]
`
`6E
`4RA
`20A8
`12
`
`18
`
`6
`
`18
`
`12
`
`18
`
`18
`
`8
`
`12
`
`73
`24
`
`[18-42]
`
`[18-42]
`
`35 [27-49]
`
`23.2 [19-30]
`
`34.9 [20-45]
`
`34.7 [20-45]
`
`34.7 [20-45]
`
`[19-22]
`
`30.5 [27-42]
`
`25 febrile adults
`25 febrile children
`
`[18-55]
`[10-14]
`
`12
`
`12
`
`7
`
`35.2 [21-52]
`
`[18-22]
`
`median 22
`
`Dose
`(no. of days)
`750mg CR
`2 x 375mg CST
`2 x 375mg UST
`500mg bid
`Active RA
`500mg bid
`Remission
`500mg bid x 14 days
`500mg bid x 4 days
`
`500mg SR fasting
`500mg SR postprandial
`500mg
`250mg qid x 7 days
`1000mg SR qd x 7 days
`500mg bid x 7 days
`500mg CR
`500mg CR
`500mg CR
`500mg
`500mg + standard meal
`2 x 1 9 chewable sucralfate +
`500mg 30 minutes after
`750mg
`750mg CR
`750mg CR
`375mg
`500mg
`750mg CR qd x 7 days
`375mg bid x 7 days
`500mg bid x 7 days
`250mg
`250mg EC fasted
`250mg ECfed
`750mg
`750mg CR
`750mg CR qd x 6
`500mg tablet
`500mg suspension
`250mg tablet
`250mg suspension
`70mg CR fasting
`750mg CR postprandial
`500mg 10:00h
`500mg 22:00h
`1000mg EC fasting
`1000mgfed
`
`Cmax
`(mg/L)
`42.9
`97.3
`98.6
`84.2
`
`105.1
`
`88
`110
`
`40.8
`38.2
`71.0
`99.5
`110.7
`101.8
`45.8
`45.4
`47.3
`71.2
`67.4
`53.9
`
`106.18
`63.06
`62.35
`56.69
`65.53
`100.5
`87.62
`95.08
`23.9
`19.4
`21.0
`88.9
`59.5
`76.3
`66.3
`53.8
`47.2
`49.7
`69.6
`59.9
`81.71
`70.458
`106
`103
`
`tmax
`(h)
`11.8
`2.4
`2.3
`2.22
`1.84
`1.86
`1.46
`NR
`NR
`
`5.08
`10.3
`1.58
`0.89
`1.36
`5.00
`11.0
`8.7
`9.3
`2.2
`1.9
`4.1
`
`3.25
`4.35
`4.0
`2.06
`3.06
`3.44
`2.39
`1.83
`7.1
`7.2
`10.4
`1.8
`5.3
`4.5
`2.9
`2.2
`3.3
`2.4
`4.08
`5.0
`1.36
`2.70
`5.0
`6.0
`
`AUC
`(mg/L. h)
`1524.3
`1488.4
`1491.3
`NR
`NR
`NR
`NR
`694
`896
`
`1118.7
`1156.1
`1033.0
`1640.6
`1580
`1560
`1393
`1258
`1400
`1122.2
`1131.4
`1148.4
`
`1808.73
`1990.43
`2010.07
`793.48
`973.86
`1741.47
`751.54
`876.72
`677
`678
`661
`1547
`1682
`1313
`734.5
`692.1
`572
`548
`1978.7
`1778.6
`1434.8
`1482.9
`NR
`NR
`
`Reference
`
`44
`
`28
`
`45
`
`46
`
`46
`
`47
`
`48
`
`49
`
`49
`
`49
`
`50
`
`51
`
`52
`
`53
`
`54
`
`55
`
`© Adis International Urnited. All rights reserved.
`
`Clin. Pharrnacokinet. ·19Q7 Apr; 32 (4)
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 5
`
`

`

`Naproxen
`
`Table I. Contd
`
`No. of patients
`(type)
`10
`MA
`
`12
`
`10
`
`6
`
`14
`
`24
`
`23C
`
`24
`
`Agea (y)
`[range]
`[25-57]
`
`[24·42]
`
`[20-50]
`
`[20·50]
`
`22.1
`
`[22·47]
`
`[8-14]
`
`27 [18-38]
`
`28
`
`[21·44]
`
`Dose
`(no. of days)
`500mg with attacks
`500mg without attacks
`250mg
`250mg supp
`500mg
`500mg and cimetidine 400mg bid
`500mg
`500mg; cim 400mg bid
`500mg; ran 150mg bid
`500mg; fam 20mg qd
`500mg caplet
`500mg tablet
`500mg EC
`500mg
`250mg tablet
`250mg suspension
`500mg alone day 16
`500mg + zileuton 800mg day 10
`500mg + placebo day 10
`500mg alone day 16
`250mg
`500mg
`
`Cmax
`(mg/L)
`68.9
`70.6
`46.1
`41.2
`61.5
`59.7
`61
`58
`68
`65
`77.9
`71.4
`94.9
`97.4
`68.5
`54.6
`113
`112
`99
`104
`35.48
`64.05
`
`tmax
`(h)
`2.89
`1.89
`1.3
`1.7
`1.3
`1.2
`1.4
`1.4
`1.4
`1.4
`1.02
`1.5
`4.0
`1.9
`2.67
`2.16
`1.3
`1.8
`2.0
`1.6
`2.86
`2.25
`
`AUC
`(mg/L· h)
`786.2
`695.4
`691
`668
`NR
`NR
`1060
`846
`1064
`984
`1210.2
`1211.0
`845.0
`766.8
`703
`659
`869
`903
`780
`829
`560.5
`942.24
`
`273
`
`Reference
`
`5
`
`56
`
`57
`
`57
`
`58
`
`59
`
`60
`
`61
`
`62
`
`a Mean age; range in parentheses.
`Abbreviations: AC = alcoholic cirrhosis; AIOH = aluminum hydroxide; AUC = area under the concentration-time curve; bid = twice daily;
`C = children; Cmax = peak plasma drug concentration; CR = controlled release; CSM = cholestyramine; CST = Canadian standard tablets;
`CW = Carbowax; OM = diabetes mellitus; E = elderly; EC = enteric coated; HF = healthy fasted; HNF = healthy non-fasted; MA = migraine
`attacks; MgOH = magnesium hydroxide; MRF = moderate renal failure; NH = neoplastic hypoproteinemia; NR = not reported; PB = probenecid;
`qd = daily; qid = 4 times daily; q6h (q12h) = every 6 (12) hours; RA = rheumatoid arthritis; RI = renal insufficiency; SIM = simethicone; SRF
`= severe renal failure; SGT = sulglycotide; supp = suppository; tmax = time taken to achieve Cmax; UST = United States standard tablets; WS
`= whitesupol.
`
`a lower Cmax and a delayed time to attain maximum
`concentrations (tmax). [25,35,38,44,46,47,49-51 ,58,59,61,67] Napro-
`xen is rapidly and well absorbed by the lower in(cid:173)
`testinal tract from suppositories,l12,14,26,42,56,68,69]
`The absorption is significantly faster for naproxen
`sodium suppositories when compared with bio(cid:173)
`equivalent naproxen tablets,l34] The rate of absorp(cid:173)
`tion and the bioavailability are significantly higher
`for naproxen sodium suppositories when com(cid:173)
`pared to naproxen free acid suppositories.[26] The
`vaginal absorption of naproxen was investigated in
`5 healthy pre-menopausal women, the study dem(cid:173)
`onstrated that naproxen was absorbed, but not to
`therapeutically useful concentrations,l34] After cu(cid:173)
`taneous application of gels containing naproxen
`
`the drug is absorbed slowly, reaching a Cmax 24
`hours after application; bioavailability is between
`1 and 2.1%.[70]
`
`1. 1.2 Effects of Food
`Several studies[55,63,64] indicate that the intake
`of food delays the absorption of naproxen, possibly
`by delaying the stomach emptying time coupled
`with slow gastric absorption. One study[48] indicates
`that administration of a standard meal with napro(cid:173)
`xen is accompanied by a significant increase in the
`rate of absorption, without any significant change
`in other pharmacokinetic variables when com(cid:173)
`pared with naproxen alone.
`An increase in gastrointestinal pH following
`food intake may facilitate dissolution of naproxen
`
`© Adis International Limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Apr; 32 (4)
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 6
`
`

`

`274
`
`Davies & Anderson
`
`and accelerate the rate of absorption which, by
`analogy, can be compared to the acceleration of
`naproxen absorption when taken with sodium bi(cid:173)
`carbonate.f711 Differences between protocols may
`account for the differential effects of food in these
`studies. For example, in the initial study by Runkel
`et al.,l63) naproxen was administered as a suspen(cid:173)
`sion in the middle of a fatty meal. The rate and
`extent of absorption of a naproxen controlled(cid:173)
`release tablet is not substantially altered by the in(cid:173)
`gestion of food.[46) However, in one study[53) the
`Cmax decreased by about 14% when taken with
`food and, conversely, increased by 37% with food
`in another study,l43] indicating the necessity of dis(cid:173)
`tinguishing between different controlled-release
`formulations and/or diets.
`
`1. 1.3 Effect of Different Disease States
`Different disease states may affect naproxen ab(cid:173)
`sorption. For example, post-operative patients have
`demonstrated a reduction in gastrointestinal ab(cid:173)
`sorption.122] Drug absorption may be slightly de(cid:173)
`layed during migraine attacks, which may be related
`to delayed gastric emptying, and could potentially
`delay the onset of analgesic effects.l5) Patients with
`chronic hepatic impairment having underlying chol(cid:173)
`estasis show a significant decrease in the rate of
`absorption. (19) In addition, patients with severe di(cid:173)
`abetic microangiopathy show evidence of a 30%
`decrease in the fraction of dose absorbed.[17] How(cid:173)
`ever, absorption characteristics after both single
`and multiple doses are not significantly different in
`rheumatic disease states.157)
`
`1. 1.4 Drug Interactions
`Antacids containing magnesium oxide, alumi(cid:173)
`num hydroxide and, to a lesser extent, magnesium
`carbonate appear to interfere with naproxen ab(cid:173)
`sorption through the formation of poorly diffusible
`complexes.[71) However, a mixture of aluminum
`hydroxide/magnesium hydroxide and simethicone
`with and without naproxen after single and multi(cid:173)
`ple doses in healthy volunteers did not appear to
`affect the bioavailability of naproxen. [21) Concom(cid:173)
`itant administration of cholestyramine resin causes
`a zero-order absorptive process due to binding of
`naproxen.l24) Sucralfate may delay the tmax of
`
`naproxen, but does not affect bioavailability.[32,33,52)
`The concomitant intake of the H2-histamine antag(cid:173)
`onists (e.g. cimetidine, ranitidine and famotidine)
`does not appear to interfere with the absorption
`process.[n,73)
`
`1.1.5 Circadian Rhythm
`The influence of chronobiology has demon(cid:173)
`strated a decrease in Cmax and a delay in tmax , with
`a corresponding lower absorption rate constant af(cid:173)
`ter a 22:00 hour dose when compared to a 10:00
`hour dose, which is attributed to decreased gastric
`pH coupled with the poor water solubility of
`naproxen, retarded intestinal motility and lower
`blood flow at night. [54]
`
`1 .2 Distribution
`
`Table II summarises the pharmacokinetic prop(cid:173)
`erties of naproxen in healthy volunteers.
`The apparent volume of distribution (V d/F) , de(cid:173)
`termined after oral administration, is between 5 and
`lOL in humans (0.1 to 0.2 Llkg), which approxi(cid:173)
`mates plasma volume and is consistent with other
`2-APA NSAIDs.l6,8,IO,II) However, since protein
`binding is concentration-dependent, the estimated
`V d/F will vary with changes in protein binding.
`
`1.2. 1 Protein Binding
`Naproxen is extensively (>99.9%) bound in
`plasma, serum and in solutions of human serum albu(cid:173)
`min with high affinity (K = 5-8 x 106 Llmol) and
`large capacity at therapeutic concentrations.!75-77)
`In human plasma and in solutions of albumin, at
`concentrations similar to human plasma, naproxen
`binding is high and not modified by pH variations
`(5 to 7.8) or albumin concentrations (1 to 7 g/100ml).
`At a plasma concentration of 100 mg/L, the degree
`of protein binding is 99% (96% bound to albumin),
`whereas at a concentration of 500 mg/L the respec(cid:173)
`tive percentages were 93 and 87%.
`Naproxen is principally bound to albumin but
`also appears to be bound to globulins;[78) it binds
`significantly to salivary proteins but to a lower ex(cid:173)
`tent (66% ).!79) Consequently, naproxen is primarily
`confined to the central compartment, reflected by
`its relatively small V d/F (0.1 to 0.2 Llkg), which is
`
`© Adis International Limited . All rights reserved.
`
`Clin, Pharmacokinet, 1997 Apr: 32 (4)
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 7
`
`

`

`Naproxen
`
`275
`
`Table II. Pharmacokinetic properties of naproxen in healthy volunteers (orallR dosage forms administered in single doses, except where
`indicated)
`
`No. of
`patients
`6
`6
`
`Age" (y)
`[range]
`NR
`23 [22-25]
`
`16
`
`20 [18-23]
`
`6
`
`12
`
`7
`11
`
`12
`
`12
`
`8
`11
`
`6
`
`10
`
`10
`
`10
`
`7
`
`6
`
`NR
`
`NR
`
`26.6 [23-43]
`28 [21-39]
`
`[23-42]
`
`[23-42]
`
`28
`[19-25]
`
`[20-54]
`
`[20-52]
`
`[20-52]
`
`29 [22-39]
`
`23 [19-28]
`
`24.3 [21-30]
`
`12
`
`[18-27]
`
`6
`
`14
`
`14
`
`[21-30]
`
`[22-30]
`
`[22-30]
`
`Dose
`(no. of days)
`100-300mg
`500mg
`500mg supp
`1000mg
`2000mg
`3000mg
`4000mg
`500mg
`500mg and 1 9 PB qid day 1 and
`500mg qid on days 2 and 3
`Sequence 2
`250mg bid x 7 days and PB 500mg bid
`x 7 days
`250mg bid x 7 days
`
`tl,;,
`(h)
`13.9
`10.25
`10.25
`13.75
`13.75
`13.75
`14.25
`13.9
`36.7
`
`Vd/F
`(Ukg)b
`0.09
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`
`17.3
`
`NR
`
`12.5
`14.91
`16.4
`16.1
`
`250mg
`250mg
`250mg + AIOH, 200 mg/ml; MgOH,
`200 mg/5ml; and SIM, 20 mg/5ml
`17.4
`250mg 1 st time
`18.8
`250mg 2nd time
`16.3
`250mg 1 st time
`16.7
`250mg 1 st time
`250mg + 4g CSMin 100ml orange juice 12.66
`500mg sodium supp
`17.2
`17.2
`500mg tablets
`500mg sodium supp
`17.3
`16.8
`500mg supp
`500mg EC
`16.7
`500mg
`16.4
`500mg EC
`16.7
`16.4
`500mg
`375mg
`NR
`NR
`375mg bid x 9 days
`1000mg qd x 4days
`12.3
`500mg bid x 4 days
`9.5
`500mg
`15.9
`500mg + sucralfate 2g
`15.7
`500mg
`15.5
`500mg + sucralfate 2g
`14.3
`500mg bid for 10 doses
`14.9
`500mg bid for 10 doses sucralfate
`14.1
`750mg CR
`19.8
`17.2
`750mg
`1000mg CR
`16.4
`500mg bid
`14.7
`14.8
`100mg CR x 7 days
`500mg bid x 7 days
`13.7
`
`NR
`0.094
`0.057
`0.052
`
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`0.125
`0.164
`0.139
`0.105
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`
`CUF
`(Uh/kg)C
`NR
`NR
`NR
`0.21
`0.21
`0.187
`0.18
`NR
`NR
`
`NR
`
`NR
`NR
`NR
`NR
`
`Reference
`
`63
`14
`
`15
`
`16
`
`16
`
`17
`21
`
`23
`
`23
`
`21
`26
`
`4.27
`3.97
`4.93
`4.30
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`0.0056
`0.0074
`0.0084
`0.0078
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`35
`NR Continued over page
`
`25
`
`25
`
`27
`
`29
`
`32
`
`33
`
`35
`
`35
`
`© Adis International Limited. All rights reserved.
`
`Clin. Phormacokinet. 1997 Apr; 32 (4)
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 8
`
`

`

`276
`
`Davies & Anderson
`
`Table II. Contd
`
`No. of
`patients
`12
`
`Age" (y)
`[range]
`32.8
`
`14
`
`26.5 [21-35]
`
`23
`
`12
`
`7
`22
`12
`
`8
`12
`
`[19-32]
`
`21 .6 [18-32]
`
`median 33 [26-36]
`34.3 [21-44]
`[25-42]
`
`24
`[18-42]
`
`18
`
`[18-42]
`
`6
`
`35 [27-49]
`
`18
`
`23.2 [19-30]
`
`18
`
`34.7 [20-45]
`
`18
`
`34.7 [20-45]
`
`12
`
`8
`
`34.9 [20-45]
`
`[19-22]
`
`12
`
`30.5 [27-42]
`
`12
`
`12
`
`35.2 [21-52]
`
`[18-22]
`
`Dose
`(no. of days)
`500mg
`500mg + SGT 200mg
`500mg bid
`1000mg CR
`500mg bid x 7 days
`1000mg CR qd x 7 days
`375mg bid x 15 doses
`750 bid x 15 doses
`750mg CR
`2 x 375mg CST
`2 x 375mg UST
`1000mg
`500mg supp
`1000mg CR fasting
`1000mg CR postprandial
`500mg bid x 4 days
`500mg SR fasting
`500mg SR postprandial
`500mg
`250mg qid x 7 days
`1000mg SR qd x 7 days
`500mg bid x 7 days
`500mg CR
`500mg CR
`500mg CR
`500mg
`500mg + standard meal
`2 x 1 9 chewable sucralfate +
`500mg 30 minutes after
`750mg CR
`375mg
`500mg
`750mg CR qd x 7 days
`375mg bid x 7 days
`500mg bid x 7 days
`750mg
`750mg CR
`250mg
`250mg EC fasted
`250mg EC fed
`750mg
`750mg CR
`750mg CR qd x 6
`750mg CR fasting
`750mg CR postprandial
`500mg 10:00h
`500mg 22:ooh
`
`\1,2
`(h)
`8.39
`7.93
`13.3
`13.9
`12.9
`13.6
`13.4
`12.2
`14.4
`16.1
`16.5
`16.8
`15.2
`17.3
`17.6
`10.08
`15.3
`19.1
`15.5
`13.0
`17.9
`13.6
`16.2
`15.6
`15.6
`15.9
`15.5
`15.0
`
`18.65
`8.47
`9.00
`21.04
`8.27
`8.99
`12.17
`21.02
`15.9
`17.8
`17.5
`17.8
`18.88
`19.9
`22.3
`20.9
`18.32
`17.15
`
`Vd/F
`(Ukg)b
`7.63
`7.9
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`0.144
`0.147
`NR
`NR
`0.11
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`
`CUF
`(Uh/kgj<
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`0.0058
`0.445
`NR
`NR
`0.0079
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`NR
`
`Reference
`
`37
`
`38
`
`40
`
`44
`
`41
`42
`43
`
`45
`46
`
`46
`
`47
`
`48
`
`49
`
`49
`
`49
`
`50
`
`51
`
`53
`
`54
`
`© Adis Interno~onol Lirnited . All rights reserved.
`
`Clin. Phormacokinet. 1997 Apr; 32 (4)
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 9
`
`

`

`Naproxen
`
`Table II. Contd
`
`No. of
`patients
`12
`
`Age" (y)
`[rangeJ
`[24-42J
`
`[20-50J
`
`[20-50J
`
`22.1
`
`[22-47J
`
`60.91 [37-79J
`
`10
`
`6
`
`14
`
`24
`
`6
`RA
`OA
`PSA
`6
`
`24
`
`27 [18-38J
`
`28
`
`[21-44J
`
`Dose
`(no. of days)
`250mg
`250mg supp
`500mg
`500mg; cimetidine 400mg bid
`500mg
`500mg; cimetidine400mg bid
`500mg; ranitidine 150mg bid
`500mg; famotidine 20mg qd
`500mg caplet
`500mg tablet
`500mg EC
`500mg
`500mg
`UPC
`SFC
`SFUC
`500 mg q12h x 7 days +
`single dose day 8
`UPC
`SFC
`SFUC
`500mg alone day 16
`500mg + zileuton 800mg day 10
`500mg + placebo day 10
`500mg alone day 16
`250mg
`500mg
`
`11,,,
`(h)
`15.1
`14.6
`25.8
`13:2
`25.7
`13.0
`16.0
`13.0
`16.7
`16.9
`16.3
`16.9
`63.5
`0.306
`18.4
`0.130
`89.1
`
`0.697
`46.9
`0.514
`11.0
`13.3
`10.4
`10.6
`12.27
`13.34
`
`Vd/F
`(Ukg)b
`NR
`NR
`NR
`NR
`0.2
`0.15
`0.11
`0.13
`NR
`NR
`NR
`NR
`2.4
`2.7
`12.2
`14.8
`1.9
`
`2.5
`5.2
`4.0
`0.117
`0.135
`0.123
`0.119
`0.115
`0.138
`
`CUF
`(Uh/kg)C
`NR
`NR
`0.00678
`0.00841
`0.0066
`0.0087
`0.0070
`0.0075
`NR
`NR
`NR
`NR
`1022
`3.31
`710
`4.26
`769
`
`4.38
`501
`4.93
`0.0070
`0.0081
`0.0075
`0.0072
`0.0066
`0.0079
`
`277
`
`Reference
`
`56
`
`57
`
`57
`
`58
`
`59
`
`74
`
`61
`
`62
`
`a Mean age; range in parentheses.
`b Vd/F = apparent volume of distribution after oral administration.
`c CUF = plasma clearance of drug after oral administration.
`Abbreviations: AIOH = aluminum hydroxide; C = children; CR = controlled release; CSM = choleslyramine; CST = Canadian standard tablets;
`CW = Carbowax; EC = enteric coated; MgOH = magnesium hydroxide; NR = not reported; OA = osteoarthritis; PB = probenecid; PSA =
`psoriatic arthritis; qd = daily; qid = 4 times daily; q6h = every 6 hours; q12h = every 12 hours; RA = rheumatoid arthritis; SFC = synovial fluid
`concentrations; SFUC = synovial fluid unbound concentrations; SIM = simethicone; SGT = sulglycotide; supp = suppository; tl", = elimination
`half-life; UC = unbound concentrations; UST = United States standard tablets; WS = whitesupol.
`
`similar to that of other chemically related NSAID
`structures.[6,IO,111
`Unconjugated O-desmethylnaproxen is fully
`bound to plasma proteins. Binding of acylglucu(cid:173)
`ronides is less; 92% for naproxen acylglucuronide,
`66% for naproxen isoglucuronide, 72% for 6-des(cid:173)
`methylnaproxen acylglucuronide and 42% for 6-
`desmethylnaproxen isoglucuronide.[571
`The plasma naproxen free fraction increases
`with increasing concentrations of the drug in the
`
`23 to 800 mg/L range, resulting in a nonlinear AUC
`with increasing doses above 500mg.P4,80-821 Al(cid:173)
`though these results have been confirmed by other
`investigators, the actual free fraction values are
`considerably lower than those initially reported by
`Runkel et al)831 This may be due to differences in
`analytical methodology or between plasma and
`serum protein binding.
`A recent study also demonstrates nonlinearity in
`synovial fluid protein binding. Naproxen synovial
`
`© Adis International Limited. All rights reserved.
`
`Clin. Pharmacokinet. 1997 Apr; 32 (4)
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 10
`
`

`

`278
`
`Davies & Anderson
`
`fluid protein binding is concentration-dependent
`between 10 and 100 mg/L.[74]
`The protein binding of naproxen is dependent
`on the amount and nature of circulating protein,
`especially albumin, which may decrease in renal
`and liver disease and is lower in synovial fluid.
`Changes in protein binding are also attributable to
`an accumulation of endogenous substances, such
`as organic acids. Protein binding is significantly
`lower in patients with impaired renal function with
`increased serum urea, serum creatinine and total
`protein concentrations, and a relative increase in
`naproxen free fraction as well as in unbound con(cid:173)
`centrations are evident in severe renal failure.l81]
`Protein binding has also been shown to be re(cid:173)
`duced in patients with arthritis and hyopalbumin(cid:173)
`aemia,[15] and in patients with various hepatic
`diseases.[82] In contrast, the degree of plasma pro(cid:173)
`tein binding remains constant in patients with neo(cid:173)
`plastic hypoproteinaemia. [20]
`
`1.2.2 Synovial Fluid Distribution
`The synovium is the proposed site of action for
`NSAIDs in various rheumatic diseases. Substantial
`concentrations of naproxen have been detected in
`synovial fluids and synovial tissue of patients with
`rheumatoid arthritis and osteoarthritis.[39,74,84.89]
`Naproxen concentrations were determined in artic(cid:173)
`ular tissues at steady state and have been shown to
`concentrate in the synovial membrane and joint
`capsula rather than in bone and cartilage.[90]
`The synovial fluid studies indicate that naproxen
`has a longer tmax , a lower Cmax and a longer elimi(cid:173)
`nation half-life (tY2) in synovial fluid when com(cid:173)
`pared with plasma,l39,74,85.88] One study suggests
`. that the elimination tY2 is longer in rheumatoid ar(cid:173)
`thritis but not in osteoarthritis,[86] which contrasts
`with the findings of other studies investigating pa(cid:173)
`tients with osteoarthritis.[39,87] Concentrations of
`6-desmethylnaproxen are reported to be extremely
`low in all synovial fluid samples.[39] After repeated
`oral doses of naproxen, steady-state peak concen(cid:173)
`trations in synovial fluid are reported to be 65% of
`that in plasma,[39,74] or even higher in synovial
`fluid,[87] with a ratio of synovial fluid to plasma
`concentration of 2.4.
`
`The average AUC of unbound naproxen in
`plasma and synovial fluid was the same over a dos(cid:173)
`age interval at steady state, but were not the same
`after a single dose, where the mean unbound syno(cid:173)
`vial fluid AUC was 1.2 times the mean unbound
`plasmaAUC.[74] Free fractions of naproxen are sig(cid:173)
`nificantly higher in synovial fluid (0.14%) when
`compared with plasma (0.11 %), which is likely to
`be due to lower albumin concentrations in synovial
`fluid.[74,77]
`The clinical effectiveness, as demonstrated by
`decreases in morning stiffness and Lee Index
`scores (a functional index of rheumatoid arthritis),
`appears to correlate with the free concentration of
`naproxen in synovial fluid.l91 ] However, a more re(cid:173)
`cent investigation demonstrated that whereas pros(cid:173)
`taglandin E2 concentrations were low after both
`short and long term admin