Br. J. clin. Pharmac. (1980), 10, 259-263
`
`BIOA V AILABILITY OF
`NAPROXEN SODIUM AND ITS
`RELATIONSHIP TO CLINICAL ANALGESIC EFFECTS
`
`H. SEVELIUS, R. RUNKEL, E. SEGRE & S.S. BLOOMFIELD
`The Institutes of Clinical Medicine and Pharmacology and Metabolism, Syntex Research, Palo Alto, California and
`Division of Clinical Pharmacology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
`
`In the first of a series of trials with naproxen sodium it was shown that patients achieved
`1
`significantly earlier and higher plasma levels of naproxen when naproxen sodium was administered.
`In a second study comparing naproxen with naproxen sodium in patients with post-partum pain,
`2
`pain intensity was consistently lower for the group receiving naproxen sodium. However, statistically
`significant differences were not seen until 4 or 5 h after medication.
`3 A final study documented that a more frequent dosage schedule of every 6 h led to clearly higher
`plasma levels than those achieved with an every 8 h regimen; plasma levels did not plateau. Doses up
`to 1,375 mg/day were well tolerated.
`4
`In conclusion, naproxen sodium appears to be an improved form of naproxen for use as an
`analgesic agent.
`
`Introduction
`
`Naproxen is a nonsteroidal agent with demonstrated
`and
`antipyretic
`anti-inflammatory,
`analgesic
`properties (Roszkowski, Rooks, Tomolonis, Miller &
`Pelczarska, 1973). Studies with single 200 to 600 mg
`doses of naproxen have shown it to be at least as
`effective as single standard doses of aspirin or other
`standard reference analgesics
`in patients with
`moderate or severe postoperative pain resulting from
`ortfiopaedic (Ruedy & McCullough, 1973), dental
`(Ruedy, 1973), and other surgical procedures
`(Mahler, Forrest, Brown, Shroff, Gordon, Brown &
`James, 1976; Stetson, Robinson, Wardell & Lasagna,
`1973). The need for an analgesic agent with an even
`faster onset of action than naproxen, however, has
`led to an investigation of methods to increase the
`speed of absorption of naproxen.
`If it is true that a certain minimum effective plasma
`concentration is necessary for analgesic activity, then
`it follows that a more rapidly absorbed dosage form
`should provide a more rapid onset of activity
`(Swarbrick, 1973). Alkali metal salts of weak organic
`acids are known to dissolve more rapidly in aqueous
`solutions than the corresponding weak acid itself'
`(Wagner, 1975). The rate at which a drug dissolves in
`the gastrointestinal tract often partially or completely
`controls the rate at which the drug appears in the
`blood (Levy, 1961). Accordingly, since naproxen is a
`weak acid (pKa = 4.15), the sodium salt of naproxen
`was developed since it logically represented one of the
`
`best means of providing more rapid absorption of
`naproxen and, thereby, an earlier effect. A series of
`studies was then designed to evaluate the bioavailability
`and efficacy of naproxen sodium.
`First
`the pharmacokinetics of naproxen and
`naproxen sodium were compared to determine
`whether the sodium salt was more rapidly absorbed.
`Then an analgesic study was conducted to determine
`whether any such differences in absorption rates were
`clinically significant (Bloomfield, Barden & Mitchell,
`1978). While the rate of absorption may affect the
`onset of analgesic activity, continued plasma levels of
`the drug are likely to be important in maintaining
`analgesia. Therefore, the steady state plasma levels of
`naproxen sodium associated with two different dosage
`regimens were measured in a third study.
`
`Methods
`
`Bioavailability (naproxen v naproxen sodium)
`
`Twelve healthy male volunteers participated in this
`study. All study subjects were within 10"/o of the
`average weight for their age, sex and height as
`determined by the Metropolitan Life Insurance
`Company weight tables. At the beginning and end of
`the study, each volunteer underwent a complete
`physical examination
`including
`routine blood
`
`0306--5251/80/100259-05 $01.00
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`260
`
`H. SEVELIUS ET AL
`
`chemistry determinations. During the study, any
`the subjects were
`reported by
`adverse effects
`recorded. Hypnotics, sedatives, antihistamines or
`other enzyme inducing drugs were not permitted for 1
`month prior to the study, and no other drugs or
`alcohol were permitted 72 h prior to the start of the
`study and throughout the study period. Excessive
`smoking was discouraged during the trial.
`At 08.30 h of the test day, following an overnight
`fast, subjects ingested either a tablet of 500 mg of
`naproxen or the equimolar 550 mg of naproxen
`sodium with 100 ml of water (drug was assigned
`randomly). Blood (10 ml) was obtained from each
`subject at basline and 10, 20, 40, 60 min, 2, 4, 6, 8 and
`24 h after ingestion of the drug. Plasma was
`separated and frozen for later naproxen plasma level
`determinations by gas chromatography (Runkel
`Chaplin, Sevelius, Ortega & Segre, 1976). The
`subjects remained fasting until after the fourth hour
`blood sample. After a 1 week interval, they repeated
`the same procedure with the second drug in a
`crossover design.
`
`Time course of analgesia (naproxen v naproxen sodium)
`
`Sixty postpartum women with moderate or severe
`the 48 h after an
`uterine cramping during
`uncomplicated delivery participated in this study.
`This
`single-dose, double-blind parallel
`study
`evaluated the comparative analgesia of naproxen and
`its sodium salt. No other analgesic, sedative or
`psychotropic medications were permitted during the
`6 h preceding the study. None of the patients was
`breast feeding her infant.
`On demand, patients randomly received either
`500 mg naproxen or 550 mg naproxen sodium tablets
`with a glass of water. The two treatment groups were
`comparable in terms of demographic characteristics
`and degree of cramping. Each patient evaluated pain
`intensity at baseline (immediately before drug
`administration) and 15, 30, 60 min, 2, 3, 4, 5 and 6 h
`after ingestion of the drug. Pain intensity was rated
`on a scale of 0 to 3 (O=no pain, I =mild pain,
`2=moderate pain, 3=severe pain) and then Pain
`Intensity Differences (PID) were calculated by
`finding the arithmetic difference between the patient's
`baseline score and each periodic post-treatment score.
`These periodic PID scores were used to compute the
`degree of pain relief (SPID-sum of pain intensity
`differences), and, together with pain intensity scores,
`were used to measure onset, peak, and duration of
`pain relief. SPID scores have been shown to be an
`appropriate and valid
`technique
`to evaluate
`analgesics (Bellville, Forrest & Brown, 1968; Houde,
`Wallenstein & Rogers, 1960).
`Any adverse effects reported during the study
`peri.:>d were recorded.
`
`Steady state plasma levels (two dosage regimens of
`naproxen sodium)
`
`Sixteen healthy volunteers (8 males and 8 females)
`participated in this study. None received any enzyme
`inducing drugs during the month prior to the study.
`Subjects did not alter their daily activities or dietary
`habits. All volunteers were within 10% of average
`weight for their age, sex and height.
`Each subject received a loading dose of naproxen
`sodium (550 mg) at 09.00 h on the test day.
`Thereafter, subjects
`ingested 275 mg naproxen
`sodium either every 6 h or every 8 h, for a total of 3
`consecutive days
`(drug
`regimen was assigned
`randomly). Ten millilitres of blood was obtained at
`baseline and 4, 8, 24, 32, 48, 52, 56 and 72 h after
`ingestion of the drug. Plasma was separated and
`frozen for later naproxen plasma level determinations
`by gas chromatography. After a 10-day interval,
`subjects repeated the same procedure with the second
`dosage regimen.
`Routine blood chemistry determinations were
`performed on all subjects before and after the study,
`and any adverse effects reported during the study
`period were recorded.
`
`Results
`
`Bioavai/ability
`
`Two variables were of primary interest in this study:
`the rate of absorption of the drug, measured by the
`upslope of the drug concentration over time curve,
`and the total absorption, as characterized by the area
`under that curve. For a drug such as naproxen
`sodium which is primarily intended as an analgesic,
`the rate of absorption is particularly important.
`Naproxen sodium resulted in significantly earlier
`and higher plasma levels for the first 2 h. At 20
`and 40 min after administration,
`the plasma
`concentrations
`of
`naproxen
`sodium were
`approximately twice as high as those of naproxen
`(Figure
`I). These differences were statistically
`significant (P < 0.005 and P < O.Ql, respectively).
`One hour after adminstration the plasma level of
`naproxen sodium was still approximately 39% higher
`than the plasma level of naproxen (P < 0.01). As can
`be seen in Figure 1, the mean time to peak plasma
`level was I h for naproxen sodium and 2 h for
`naproxen, with
`the sodium salt achieving a
`significantly higher peak (P < 0.01). After 2 h, the
`plasma levels for the two drugs were approximately
`equal.
`The area under the plasma curve was significantly
`larger for naproxen sodium during early time periods,
`i.e., 33% larger during the 0 to 2 h time period
`(P < 0.01). The total absorption of naproxen and
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1027, Pg. 2 of 5
`
`

`

`70
`
`60
`
`~50
`~
`Ql
`~ 40
`Ill
`E
`
`r::::
`CD
`
`<ll -a 30
`X e 20
`a.
`Ill z
`
`"
`r/
`I
`I
`I
`I
`
`?
`
`I
`I
`I
`I
`I
`I
`
`10
`
`I
`
`o~---L----~2----~3~---4~--~s----~6
`
`Time (h)
`
`Figure 1 Naproxen plasma levels after administration
`of 500 mg naproxen ( 0) or the equimolar 550 mg
`naproxen sodium (e) to 12 healthy men in a crossover
`study. Significantly earlier and higher naproxen levels
`were achieved after naproxen sodium.
`
`naproxen sodium, as indicated by the total areas
`under the curve, was equal.
`No clinically significant adverse effects were noted
`during the study.
`
`Time course of analgesia
`
`There were no differences between the 30 patients
`who received naproxen and the 30 who received
`naproxen sodium with respect to age distribution,
`type of labor and delivery, premedication, initial
`severity of pain or any other baseline parameter
`measured.
`Mean pain intensity scores during the study are
`illustrated in Figure 2. On the average, patients in
`both groups obtained greater than a 50"/o reduction in
`initial pain (24 of 30 in the naproxen sodium group
`and 25 of 30 in the naproxen group). However,
`naproxen sodium resulted in consistently lower mean
`pain intensity scores than did naproxen.
`intensity
`Figure 3 illustrates
`the mean pain
`differences (PID) for the two groups. At all time
`points, except 1 h, the PID scores were higher for
`the naproxen sodium group (i.e., greater pain relieO
`than for
`the naproxen group. However,
`these
`differences between the naproxen and naproxen
`sodium groups became statistically significant only 4
`and 5 h after administration of medication. The
`
`BIOA V AILABILITY OF NAPROXEN SODIUM
`
`261
`
`<ll
`
`l!! 3.5
`
`., i ~3.0
`
`~ 2.5
`·u; ~
`5i Gi 2.0
`E"8
`-~ ~ 1.5
`"iii "C
`~ ~ 1.0
`l3
`~ 0.5
`
`0-~~~----~--~----~--~--~
`0.250.5
`6
`3
`2
`4
`5
`Time (h)
`
`Figure 2 Mean pain intensity scores before and after
`administration of 500 mg naproxen ( 0) or the
`equimolar 550 mg naproxen sodium (e) to 30
`postpartum women with moderate or severe uterine
`cramps. Scores were consistently lower for those patients
`receiving naproxen sodium.
`
`naproxen sodium group achieved a peak PID score of
`2.37 in the fifth hour, while the naproxen group
`achieved a lower peak PID score (2.00) in the third
`hour. The sum of pain intensity differences (SPID)
`was also greater for the naproxen sodium group than
`for the naproxen group. These data suggest that
`naproxen sodium resulted in better analgesia than
`naproxen in this clinical setting.
`No clinically significant side effects were noted
`during the study.
`
`Steady state plasma levels
`
`More frequent dosing (i.e., larger total dose of drug
`ingested) was reflected in higher mean plasma levels
`of naproxen. Those patients on the every 6 h regimen
`achieved mean naproxen plasma levels approximately
`20 ,ug/ml higher than those on every 8 h regimen (Figure
`4). Differences between the two regimens at 24, 48 and
`72 h were highly statistically significant (P < 0.001).
`No clinically significant adverse effects were noted
`during the study.
`
`Discussion
`
`The results of the first study document the theoretical
`advantages of utilizing the sodium salt ofnaproxen to
`achieve more rapid absorption of the drug. Patients
`achieved significantly earlier and higher plasma levels
`of naproxen with naproxen sodium.
`This improved bioavailability was not immediately
`evident, however, in a clinical setting. Both those
`
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`
`

`

`262
`
`H. SEVELIUS ET AL
`
`I
`A.. P=0.05 P=O.Ol
`....
`....
`I
`I
`''0-----o---o
`
`2.5
`
`0 a: 2.0
`gj
`0
`c:
`~
`(I)
`:t:
`'6
`~
`·~ 1.0
`~
`.!:
`c:
`'(ij
`c... 0.5
`
`550
`I
`
`275 275 275 275 275 275 275 275 275 275
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`10.....-...
`
`I?--......._,
`
`'
`
`f-."1/..
`p
`I
`' 'd' .P.
`.......... ..._ cf
`.. ....... ..o ........ o .................. .o
`
`'
`'o
`
`···~./1···0
`v
`
`t
`275
`
`24
`
`t
`t
`275 275
`
`32
`Time (h)
`
`t
`t
`275
`275
`485256 ~2
`
`E 80
`
`70 ~ --
`f.
`-
`60
`~
`j! 50
`i....
`~ 40 t ··a...
`<11
`-a. 30 (
`(
`X e 0.
`<11 z
`
`c:
`(I)
`
`20
`10 i
`t
`550
`
`t
`275 275
`
`4 8
`
`2
`
`3
`Time (h)
`
`6
`
`intensity differences
`Figure 3 Mean pain
`(PID;
`arithmetic differences between baseline and each post(cid:173)
`treatment score) after administration of 500 mg
`naproxen (0) or 550 mg naproxen sodium (e) to 30
`postpartum women with moderate to severe uterine
`cramps.
`
`patients who received naproxen and those who
`received naproxen sodium noted a rapid reduction in
`pain. The early differences between the two groups
`were small, and statistically significant differences in
`analgesic response were not seen until 4 and 5 h after
`medication. However, pain is a very subjective
`variable, and statistically significant differences are
`notoriously difficult to achieve between two active
`analgesic agents. Nonetheless, pain intensity was
`consistently lower for the group receiving naproxen
`sodium, even 15 min after administration. It may be
`that much larger numbers of patients are necessary to
`demonstrate
`statistically
`significant differences,
`particularly during the first hours of study. This
`remains to be resolved by future studies.
`In two earlier studies of analgesics in patients with
`to
`postpartum pain (one comparing naproxen
`placebo and codeine and the other comparing
`naproxen sodium to placebo and aspirin), statistically
`significant differences between naproxen or naproxen
`sodium and placebo were seen only 2 to 3 h after
`medication (Bloomfield, Barden & Mitchell, 1977).
`The dose of naproxen was 300 or 600 mg and the dose
`of naproxen sodium was 275 mg
`(half
`the
`recommended therapeutic dose). However,
`in a
`separate study using the full therapeutic dose of
`naproxen sodium (550 mg), patients with pain of
`varying origin (musculoskeletal, dental, headache,
`etc.) found naproxen sodium significantly superior
`
`Figure 4 Comparison of the mean naproxen plasma
`levels between naproxen sodium administered every 6 h
`(0----0) or every 8 h (0""0) to 16 healthy men and
`women in a crossover study. The every 6 h regimen
`produced average naproxen plasma levels approximately
`20 11g/ml higher than the every 8 h regimen.
`
`to both placebo and aspmn I hour after dosing
`(Sevelius, Segre & Bursick, 1980).
`is
`sodium
`Whether naproxen or naproxen
`administered, the circulating moiety is the same, and
`the two drugs thus share the same long biological
`half-life (13-14 h). This long half-life is particularly
`useful when naproxen is used for chronic anti(cid:173)
`inflammatory
`therapy, since
`the drug can be
`administered on a twice daily regimen and still reach
`adequate steady-state plasma levels to maintain
`therapeutic efficacy. In addition, using a single dose of
`naproxen sodium, a previous study demonstrated a
`sustained duration of analgesic effect for up to 7 h
`(entire
`length of follow-up period
`in
`study)
`(Bloomfield eta/., 1977).
`For analgesia, it may be desirable to reach quickly
`and maintain high plasma levels in order to obtain
`fast and continuous maximum therapeutic benefits.
`The more rapid bioavailability of the sodium salt of
`naproxen was shown in the first study. The final study
`documented that a more frequent dosage schedule of
`every 6 h led to clearly higher plasma levels than
`those achieved with an every 8 h regimen. This study
`did not evaluate the potential therapeutic benefits of
`more frequent dosing. It did demonstrate, however,
`that when more drug was ingested plasma levels
`increased. While many patients may receive rapid and
`good pain relief with an every 8 h regimen, others
`may receive added benefit from the higher plasma
`levels achieved with an every 6 h regimen. Individual
`patient variations in response to pain and initial level
`of pain make it difficult to draw any conclusions for
`
`Petitioner - Catalent Pharma Solutions
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`
`

`

`even the 'average' patient. However, further studies
`may help clarify this question.
`Including the loading dose of 550 mg, the total
`daily dosage in the final study was 1,375 mg/day and
`1,100 mg/day for the every 6 and every 8 h regimens,
`respectively. The ability to tolerate doses in this range
`was evaluated in an earlier study with naproxen
`during which single doses of 1, 2, 3 or 4 g were
`administered to 16 healthy volunteers (Runkel eta/.,
`1976). Aside from 1 person who reported mild
`epigastric pain after receiving 3 g of naproxen, no
`other subjects reported any side effects. In addition,
`there were no abnormal findings on physical
`examination nor were there any clinically meaningful
`changes in blood chemistry values. These high doses
`of naproxen were quickly cleared by the kidney
`without saturating any of the body's eliminating
`mechanisms. In another study, healthy subjects
`received 1,800 mg/day of naproxen for 30 days
`without significant side effects or changes
`in
`laboratory values
`(unpublished data, Syntex
`Corporation). In contrast, studies have shown that
`doses of 1 g or more of aspirin result in salicylate
`accumulation and a threat of salicylate intoxication
`(Levy, 1965; Wagner, 1971).
`
`References
`
`BIOA V AILABILITY OF NAPROXEN SODIUM
`
`263
`
`Thus, the regimens employed in our study (550 mg
`naproxen sodium as a loading dose, followed by 275
`mg every 6 or 8 h appear to fall within a range which
`is well tolerated in man. It has the advantage of
`allowing one rapidly to achieve and then maintain
`therapeutic plasma
`levels of the drug
`thereby
`minimizing fluctuations which might lead to some
`loss of analgesic effect.
`In conclusion, naproxen sodium appears to be an
`improved form of naproxen for use as an analgesic
`agent. It is more rapidly available to the body and
`appears to provide greater pain relief than naproxen.
`Earlier studies suggested that, at the doses employed
`in this study, naproxen sodium is well tolerated. The
`analgesic efficacy of naproxen sodium in single doses
`as low as 275 mg has been demonstrated previously.
`This, coupled with the long duration of efficacy for
`the recommended 550 mg dose and wide safety
`margin, should provide good flexibility in dosing for
`patients with pain of various origins. In addition,
`since many causes of pain are
`frequently
`accompanied by
`inflammation,
`the use of an
`analgesic which is also an· anti-inflammatory agent
`may provide added benefit.
`
`BELLVILLE, J.W., FORREST, W.H. Jr. & BROWN, B.W. Jr.
`(1968). Clinical and statistical methodology
`for
`cooperative clinical assays of analgesics. Clin. Pharmac.
`Ther., 9, 290-302.
`BLOOMFIELD, S.S., BARDEN, T.P. & MITCHELL, J. (1977).
`Naproxen, aspirin and codeine in postpartum uterine
`pain. Clin. Pharmac. Ther., 21, 414--421.
`BLOOMFIELD, S.S., BARDEN, T.P. & MITCHELL, J. (1978).
`Analgesia with naproxen and
`its sodium salt in
`postpartum uterine pain. Abstract No. 432, 7th
`International Congress of Pharmacology, IUPHAR,
`Paris, France.
`HOUDE, R.W., WALLENSTEIN, S.L. & ROGERS, A. (1960).
`Clinical pharmacology of analgesics. A method of
`assaying analgesic effect. Clin. Pharmac. Ther., 1,
`163-175.
`LEVY, G. (1961). Comparison of dissolution and absorption
`rates of different commercial aspirin tablets. J. pharm.
`Sci., 50, 388.
`LEVY, G. (1965). Pharmacokinetic of salicylate elimination
`in man. J. pharm. Sci., 54, 959-967.
`MAHLER, D.L., FORREST, W.H. Jr., BROWN, C.R., SHROFF,
`P.F., GORDON, H.E., BROWN B.W. Jr. & JAMES, K.E.
`(1976). Assay of aspirin and naproxen analgesia. Clin.
`Pharmac. Ther., 19, 18-23.
`ROSZKOWSKI, A.P., ROOKS, W., TOMOLONIS, A., MILLER,
`(1973). Pharmacological
`L. & PELCZARSKA, A.B.
`properties of naproxen. Scand. J. Rheum. Suppl. 2,
`12-19.
`
`RUEDY, J. (1973). A comparison of the analgesic efficacy of
`naproxen and acetylsalicylic acid-codeine in patients
`with pain after dental surgery. Scand. J. Rheum. Suppl. 2,
`60--63.
`RUEDY, J. & McCULLOUGH, W. (1973). A comparison of
`the analgesic efficacy of naproxen and propoxyphene in
`patients with pain after orthopedic surgery. Scand. J.
`Rheum. Suppl. 2, 56-59.
`RUNKEL, R., CHAPLIN, M.D., SEVELIUS, H., ORTEGA, E. &
`(1976). Pharmacokinetics of naproxen
`SEGRE, E.
`overdoses. Clin. Pharmac. Ther., 20, 269-277.
`SEVELIUS, H., SEGRE, E. & BURSICK, K.
`(1980).
`Comparative analgesic effects of naproxen sodium,
`aspirin and placebo. J. clin. Pharm., (in press).
`STETSON, J.B., ROBINSON, K., WARDELL, W.M. &
`LASAGNA, L. (1973). Analgesic activity of oral naproxen
`in patients with postoperative pain. Scand. J. Rheum.
`Suppl. 2, 50--55.
`(1973). Dosage Form Design and
`SWARBRICK, J.
`Bioavailability, pp. 63--65. Philadelphia: Lea and
`Febiger.
`WAGNER, J. G. (1971). Biopharmaceutics and Relevant
`Pharmacokinetics, ed I, p. 247. Hamilton, Illinois: Drug
`Intelligence Publications, Inc.
`of Clinical
`Fundamentals
`WAGNER,
`J.
`(1975).
`Pharmacokinetics, ed I, pp. 11-12. Hamilton, Illinois:
`Drug Intelligence Publications, Inc.
`
`(Received October 8, 1979)
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1027, Pg. 5 of 5
`
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