Hepatic and Renal Tolerability of Long-Term Naproxen Treatment in Patients With Rheumatoid Arthritis By Robert Turner Clinical and laboratory assessments of hepatic and abnormal values among the different patient groups. renal function in rheumatoid arthritis IRA) patients In both dosage groups, pretreatment incidences of who received naproxen for up to 6 months during clinically meaningful abnormalities in laboratory two randomized, double-blind studies comparing tests were similar to those in serial observations naproxen 375 mg twice daily (n = 266) with during treatment. Six patients who received naproxen 756 mg twice daily (n = 366) were ana- naproxen 375 mg twice daily and four patients who lyzed. Patient groups were segregated by dosage, received naproxen 756 mg twice daily had a hepatic duration of treatment, and age at entry (165 years v or renal clinical event or distinctly abnormal labora- 265 years), and laboratory measurements of SGOT, tory value, but only three of these withdrew because SGPT, serum creatinine (S,), and BUN were exam- of these problems. Occasional transient abnormali- ined. Records of individual patients with clinically ties of conventional laboratory tests of hepatic and meaningful abnormalities in laboratory tests or renal function occurred in some patients during adverse events of hepatic or renal origin were exam- naproxen treatment. Such abnormalities called for ined in detail. Over the duration of these studies, careful patient monitoring but generally did not war- there were no clinically meaningful changes in mean rant immediate drug withdrawal. laboratory values or differences in occurrences of c 1988 by Grune & Stratton, Inc. N APROXEN, a nonsteroidal antiinflamma- tory drug (NSAID) with analgesic proper- ties, has been administered to rheumatoid arthri- tis (RA) patients for more than a decade and has been shown to be well tolerated during both acute and chronic administration.‘** Nonetheless, several events in recent years have raised con- cerns about NSAIDs as a class and their poten- tial for adverse effects, particularly their poten- tial to adversely affect hepati? and renal func- tion.4 Additionally, special concern has been raised about the effects of NSAIDs on hepatic or renal function in elderly patients.“’ The objective of this study was to review two long-term naproxen trials, involving 586 RA patients, in which serial hepatic and renal function tests were included in the protocols. Laboratory and adverse event data collected in controlled clinical trials were analyzed for clues to the effects of naproxen on hepatic and renal function. Data Examination and Tabulation Study records were examined for evidence of drug-related adverse events of hepatic or renal origin. An adverse event was defined as (1) any patient withdrawal due to a complaint of such origin; (2) any other symptom or complaint that appeared to be of such origin; or (3) any unwanted event of hepatic or renal origin documented in a Drug Experience Report (DER, Food and Drug Administration Form 1639). If abnormal laboratory values were recorded in any of these categories, they were counted as adverse events. Although they were associated with the urinary system, complaints believed to be entirely related to urinary tract infections, cystitis, dysuria, nocturia, urinary frequency, burning sensa- tion in the bladder, WBCs in the urine, incontinence, and pyelitis were excluded, because they were not considered likely consequences of drug-induced renal injury. Likewise, edema, fluid retention, and infectious hepatitis were excluded from this account because it was anticipated that they would be identified in a more consistent manner from the selected laboratory tests that were reviewed intensively. The investi- gators further examined the complete records of each patient with any adverse event identified in this manner. METHODS Clinical and laboratory assessments of hepatic and renal function were analyzed in otherwise healthy RA patients during long-term naproxen treatment. Data were obtained from two multicenter, double-blind, clinical studies of paral- lel design comparing naproxen 375 mg twice daily with naproxen 750 mg twice daily. One study that lasted 6 months was completed; all patients with laboratory examinations during treatment were included in the analysis. The second was an ongoing study, designed to follow patients for up to 3 years. From this latter study, all patients whose entry dates provided the potential for 6 months of evaluation, and who had laboratory examinations during treatment, were included in the analysis. Study records also were examined for evidence of “clini- cally meaningful” abnormal laboratory values for SGOT and SGPT (measures of hepatic function), and serum creatinine (S,,) and BUN (measures of renal function). Laboratory measurements of total bilirubin, total protein, globulin, albu- min, and uric acid were also screened. All specimens were From the Bowman Gray School of Medicine, Winston- Salem, NC. Robert Turner, MD: Professor of Medicine, Bowman Gray School of Medicine. Address reprint requests to Robert Turner, MD, Bowman Gray School of Medicine, 300 S Hawthorne Rd. Winston- Salem, NC 27103. 0 I988 by Grune & Stratton. Inc. 0049-0172/88/l 703-2001%5.00/O Seminars in Arthriris and f?hsumatism, Vol 17, No 3, Suppl 2 (February), 1988: pp 29-35 29
Transcript
Hepatic and Renal Tolerability of Long-Term Naproxen Treatment in Patients With Rheumatoid Arthritis
By Robert Turner
Clinical and laboratory assessments of hepatic and abnormal values among the different patient groups. renal function in rheumatoid arthritis IRA) patients In both dosage groups, pretreatment incidences of who received naproxen for up to 6 months during clinically meaningful abnormalities in laboratory two randomized, double-blind studies comparing tests were similar to those in serial observations naproxen 375 mg twice daily (n = 266) with during treatment. Six patients who received naproxen 756 mg twice daily (n = 366) were ana- naproxen 375 mg twice daily and four patients who lyzed. Patient groups were segregated by dosage, received naproxen 756 mg twice daily had a hepatic duration of treatment, and age at entry (165 years v or renal clinical event or distinctly abnormal labora- 265 years), and laboratory measurements of SGOT, tory value, but only three of these withdrew because SGPT, serum creatinine (S,), and BUN were exam- of these problems. Occasional transient abnormali- ined. Records of individual patients with clinically ties of conventional laboratory tests of hepatic and meaningful abnormalities in laboratory tests or renal function occurred in some patients during adverse events of hepatic or renal origin were exam- naproxen treatment. Such abnormalities called for ined in detail. Over the duration of these studies, careful patient monitoring but generally did not war- there were no clinically meaningful changes in mean rant immediate drug withdrawal. laboratory values or differences in occurrences of c 1988 by Grune & Stratton, Inc.
N APROXEN, a nonsteroidal antiinflamma- tory drug (NSAID) with analgesic proper-
ties, has been administered to rheumatoid arthri- tis (RA) patients for more than a decade and has been shown to be well tolerated during both acute and chronic administration.‘** Nonetheless, several events in recent years have raised con- cerns about NSAIDs as a class and their poten- tial for adverse effects, particularly their poten- tial to adversely affect hepati? and renal func- tion.4 Additionally, special concern has been raised about the effects of NSAIDs on hepatic or renal function in elderly patients.“’ The objective of this study was to review two long-term naproxen trials, involving 586 RA patients, in which serial hepatic and renal function tests were included in the protocols. Laboratory and adverse event data collected in controlled clinical trials were analyzed for clues to the effects of naproxen on hepatic and renal function.
Data Examination and Tabulation
Study records were examined for evidence of drug-related adverse events of hepatic or renal origin. An adverse event was defined as (1) any patient withdrawal due to a complaint of such origin; (2) any other symptom or complaint that appeared to be of such origin; or (3) any unwanted event of hepatic or renal origin documented in a Drug Experience Report (DER, Food and Drug Administration Form 1639). If abnormal laboratory values were recorded in any of these categories, they were counted as adverse events. Although they were associated with the urinary system, complaints believed to be entirely related to urinary tract infections, cystitis, dysuria, nocturia, urinary frequency, burning sensa- tion in the bladder, WBCs in the urine, incontinence, and pyelitis were excluded, because they were not considered likely consequences of drug-induced renal injury. Likewise, edema, fluid retention, and infectious hepatitis were excluded from this account because it was anticipated that they would be identified in a more consistent manner from the selected laboratory tests that were reviewed intensively. The investi- gators further examined the complete records of each patient with any adverse event identified in this manner.
METHODS
Clinical and laboratory assessments of hepatic and renal function were analyzed in otherwise healthy RA patients during long-term naproxen treatment. Data were obtained from two multicenter, double-blind, clinical studies of paral- lel design comparing naproxen 375 mg twice daily with naproxen 750 mg twice daily. One study that lasted 6 months was completed; all patients with laboratory examinations during treatment were included in the analysis. The second was an ongoing study, designed to follow patients for up to 3 years. From this latter study, all patients whose entry dates provided the potential for 6 months of evaluation, and who had laboratory examinations during treatment, were included in the analysis.
Study records also were examined for evidence of “clini- cally meaningful” abnormal laboratory values for SGOT and SGPT (measures of hepatic function), and serum creatinine (S,,) and BUN (measures of renal function). Laboratory measurements of total bilirubin, total protein, globulin, albu- min, and uric acid were also screened. All specimens were
From the Bowman Gray School of Medicine, Winston- Salem, NC.
Robert Turner, MD: Professor of Medicine, Bowman Gray School of Medicine.
Address reprint requests to Robert Turner, MD, Bowman Gray School of Medicine, 300 S Hawthorne Rd. Winston- Salem, NC 27103.
0 I988 by Grune & Stratton. Inc. 0049-0172/88/l 703-2001%5.00/O
Seminars in Arthriris and f?hsumatism, Vol 17, No 3, Suppl 2 (February), 1988: pp 29-35 29
30 ROBERT TURNER
Table 1. Normal Ranges of Laboratory Values and
Elevations or Decreases Used to Define a Clinically
Meaningful Abnormality
Mean Values Clinically
at Entry Normal Meaningful
Laboratory Test (n - 579). Rawe Abnamality~
SGOT (U/L) 19.2 5-50 >70
SGPT W/L) 20.7 5-55 >70
Total bilirubin (mg/dL) 0.3 0.2-l .2 >1.5
Total protein (g/dL) 7.1 6.0-8.5 15 or > 10
Albumin (g/dL) 4.1 3.2-5.5 <2.8
Globulin (g/dL) 3.1 1.5-3.8 >4.2
S, (mg/dL) 0.9 0.7-1.4 >1.8
BUN (mg/dLI 15.5 7-25 >31
Uric acid (mg/dL) 5.1 2.5-7.5 >lO
*Mean baseline values for all patients. The sample size varies
slightly for each test due to missing values.
tAll specimens were processed by one central laboratory,
which provided these internal ranges of normal values for males
t55 years of age.
$A clinically meaningful laboratory abnormality was defined as
any abnormality that exceeded the established normal range of
values by an amount conservatively estimated as one that would
warrant further clinical and laboratory investigation or careful
monitoring.
processed by one central laboratory. A clinically meaningful
abnormality in laboratory data was defined as any abnormal-
ity that exceeded the laboratory’s established normal range of
values by an amount that would warrant either further
clinical and laboratory investigation or careful monitoring.
These amounts, listed in Table 1, were deliberately conserva-
tive. For each patient with any clinically meaningful labora-
tory test abnormality at any time during the studies, complete
lists of all results of the nine laboratory tests were examined
further to evaluate the hepatic and renal status of these
individuals.
For summary review, laboratory data were tabulated and
grouped into selected intervals of treatment duration as
follows: baseline (before therapy), acute (up to 8 weeks),
intermediate (up to 20 weeks), and long-term (up to 30
weeks). Summaries were prepared by treatment group, and
by age at entry (~65 years and 265 years). These summaries
of laboratory data were examined for group trends over time,
for changes from baseline, and for equivalence between
treatment and age groups.
Statistical Analyses
All statistical tests were two-tailed and were considered
significant if P < .05. Nonparametric methods were used to
test for changes in laboratory test values within groups
(Wilcoxon signed-rank): and for differences in the amount
of change between groups (Wilcoxon/Mann-Whitney).6
Demographics
RESULTS
Records of 586 patients, 425 women (73%) and 161 men (27%), were included in the analy-
sis. Their average age was 52.3 years (range, 19 to 78). Ninety-eight patients (17%) were 65
years of age or older; ten (2%) were 75 years or older. Two hundred eighty-six patients (49%), including 47 who were 65 years of age or older,
received naproxen 375 mg twice daily, and 300 patients (51%), including 51 who were 65 years
of age or older, received naproxen 750 mg twice daily. The two treatment groups were compara- ble in age and sex distribution.
Adverse Events
Six patients in the group receiving naproxen 375 mg twice daily and four patients receiving naproxen 750 mg twice daily had events of hepatic or renal origin. Table 2 lists the timing
and provides a brief description of each event. Most of these patients demonstrated no wors-
ening of their conditions due to continued naproxen treatment, and only three of them (patients no. 2, 5, and 6 in Table 2) withdrew from the study as a result of the event.
Of four patients who had renal calculi, only patient no. 1 had any indication of renal dysfunc- tion during the clinical trial. This patient had an elevation of BUN during week 5 of naproxen treatment and evidence of a urinary tract infec- tion. S,, remained normal. An intravenous pyelo- gram 3 months after withdrawal from the study
showed bilateral renal calculi likely to have ante-
Table 2. Descriptions of Adverse Events of Hepatic or
Renal Origin Experienced by Ten Patients
Treatment Group
(Patient No.)
375 mg twice daily
1 NAt Renal calculus
2
3
4
5
6
750 mg twice daily
7
8
9
10
0t 259 174
115
55
102 Renal calculus
108 Elevated S,
84 Elevated S,, BUN
107 Elevated LDH
Renal calculu&
Renal calculus
Elevated S,, BUN, uric
acid, LDH
Elevated LDH$
ProteinuriaG
*Number of days of treatment when the event was first
reported.
tNA, not available: event was not detected until 3 months
after treatment was withdrawn.
*Event was first reported at the end of the placebo run-in.
SPatient withdrew from study because of event.
LONG-TERM HEPATIC AND RENAL TOLERABILITY IN RA
dated naproxen treatment. Of the three remain- ing patients with renal calculus, one became symptomatic for renal calculus (hematuria) dur- ing the placebo washout period before naproxen administration, and one had a history of renal calculus.
Of three patients with elevated S,, alone or associated with other abnormal laboratory values as the adverse event, two (patients no. 4 and 8 in Table 2) had elevations in S,, during naproxen treatment that returned to normal by the end of treatment. Only patient no. 9 had abnormal S,, (1.8 mg/dL) and BUN (35 mg/dL) levels at the last evaluation. Prior to the study, patient no. 6 had proteinuria that apparently was associated with long-standing diabetes mellitus. He was clinically asymptomatic. Each of the three patients with elevated lactic dehydrogenase (LDH) concentrations during naproxen treat- ment had normal levels of SGOT, SGPT, and total bilirubin at the last evaluation.
Abnormalities in Laboratory Data
Table 3 shows the distribution of all patients with clinically meaningful abnormalities for the primary laboratory measures of hepatic and renal function at baseline and at each time interval. Overall, the incidence of such abnor- malities at each time interval during treatment was similar to the incidence at baseline. Further- more, the incidence of these abnormalities was similar for the two treatment groups. In addition, review of the other laboratory tests that were considered only indirect indicators of renal or hepatic dysfunction showed that the incidence of clinically meaningful laboratory abnormalities in globulin concentration at each time interval was no higher than at baseline. No patient had a
31
clinically meaningful elevation in total protein or total bilirubin. The incidence of clinically mean- ingful elevated albumin or uric acid values was 1% or less at baseline and similar at each time interval.
Serum Transaminases
Six patients had elevated SGOT during a single time interval while on naproxen treatment. These abnormal high values, like those of three other patients with abnormally elevated SGOT at baseline, decreased to values within normal limits at these patients’ last evaluations. Similar- ly, most high SGPT values were transient; seven were high at baseline only. Although 13 patients had clinically meaningful elevations of SGPT values during naproxen treatment, only three had high values at the end of 6 months of naproxen treatment, including one patient with a high value at baseline and throughout the study. None of the patients with elevated SGPT at the end of the 6-month observation period had a concurrent SGOT elevation.
SC, and BUN
Of the seven patients who had clinically mean- ingful S,, elevations, three had elevated S,, at baseline only. Of the other four patients, one had elevated S,, (and BUN) at baseline and through- out treatment. Another had sporadic elevations of S,, (and BUN) during and at the end of naproxen treatment (patient no. 9). The remain- ing two patients had transient elevations of S,, that were followed by normal values (patients no. 4 and 8).
Eighteen patients had clinically meaningful elevations of BUN during the study. Only three of these had normal BUN values at baseline
Table 3. Number of Patients With Clinically Meaningful Abnormalities* in Laboratory Measures of Hepatic and Renal Function at Baseline and During Each Time Interval
Baseline <B Weeks 8tol9Weeks 20 to 30 Weeks
375 bid 750 bid 375 bid 750 bid 375 bid 750 bid 375 bid 750 bid Laboratory Test (n - 281) h - 2981 h - 283) In - 295) h - 239) (n = 241) h - 182) (n - 178)
SGOT 2 1 3 1 2 0 0 0
SGPT 5 4 7 2 2 1 1 2 S&-l 1 3 0 1 1 2 1 1
BUN 3 3 3 3 3 6 2 4
Abbreviation: bid, twice daily.
*Clinically meaningful is defined as SGOT z-70 U/L, SGPT >70 U/L, S, r 1.8 mg/dL, BUN >3 1 mg/dL. Sample sizes at each time
interval and for each test differ because of attrition and missing data. Patients are counted in each time interval in which they had an
abnormality; thus, a patient may be counted in more than one time interval.
followed by abnormal values at the end of naproxen treatment (one of these was patient no.
9).
Trends and Changes in Laboratory Data Over Time
The mean SGOT, SGPT, S,,, and BUN at baseline and during 6 months of naproxen treat- ment are shown in Figs 1 and 2, and analysis of mean changes in these tests are summarized in Table 4. The mean SGOT and SGPT values decreased from baseline in both treatment groups, but the magnitude of the changes was too small to have any clinical implications.
Serum creatinine dropped slightly in the low- er-dosage group and increased slightly in the higher-dosage group. Although the mean increase in S,, in the higher-dosage group (+0.02
1.5
1.0
4
t
0.5
Fig 2. Treatment group mean values + 2 SEM for (A) S, and (B) BUN over time. The time scale reflects the time intervals used in Table 3.
A
SC,
8 20
Weeks of Treatment
30 Fig 1. Treatment group mean values + 2 SEM for (A) SGOT and (B) SGPT over time. The time scale reflects the time intervals used in Table 3.
mg/dL) and the difference in mean change between the two treatment groups were statisti- cally significant, the magnitude was too small to be clinically meaningful. Again, although the mean increases of BUN (1.4 and 2.3 mg/dL) and the difference in change between the two treatment groups were statistically significant, the magnitudes of these changes and the differ- ence between treatment groups were too small to be clinically meaningful.
Mean laboratory test results for SGOT, SGPT, S,,, and BUN at baseline, and the changes from baseline, are displayed in Table 5 for patients younger than 65 and for those 65 years of age or older. The patterns are similar to those observed for all patients. All differences in laboratory test results between age groups were too small to be clinically meaningful.
30
20
10
I I I I 1 I I I
0 8 20 30 0 8 20 30
Weeks of Treatment Weeks of Treatment
B
BUN
---- Nsproxen 375 mg bid Naproxen 750 mg bid
LONG-TERM HEPATIC AND RENAL TOLERABILITY IN RA 33
Table 4. Changes in Laboratory Measures of Hepatic and
Renal Function From Baseline to Last Evaluation
Labwatq Test
SGOT (U/L
Mean (SEMI
P valuet
SGPT (U/L)
Mean (SEM)
P value*
S, (mg/dL)
Mean (SEM)
P value*
BUN fmg/dL)
Mean (SEMI
P value$
*Negative values indicate a decrease from baseline: positive
values indicate an increase. The last available laboratory value
was used for each patient, including patients who withdrew from
the studies. Samples sizes for the individual tests differ slightly
due to missing data.
Change from Baseline*
Treatment Group
375 m9 bid 750 mg bid
In - 2811 (I-I = 2981 P valuet
- 2.8 (0.6) - 1.8 (0.8) .I7
.OOOl .03
-2.0 (0.9) -1.7 (1.1) .41
.04 .35
-0.01 (0.01) 0.02 (0.01) .02
.55 .Ol
1.4 (0.3) 2.3 (0.3) .Ol
.OOOl .ooo 1
TDifference between treatment groups in mean change from
baseline; Wilcoxon/Mann-Whitney test.
$Difference from baseline within each treatment group: Wil-
coxon signed-rank tests.
DISCUSSION
NSAIDs have been implicated in a number of renal and hepatic problems.3*4*7-11 While renal problems have in general been related to pro- staglandin synthetase-cyclooxygenase inhibi- tion,‘2”6 hepatic problems, especially in RA, have a more diverse pathogenesis related to disease activity,” associated problems such as Sjbgren’s syndrome,1**‘9 or concurrent remittive agent ther- apy.*’
Naproxen is a potent prostaglandin synthetase inhibitor in various animal models*‘-” and in human rheumatoid synovial microsomes.*’
While it has been associated with sporadic reports of problems such as pyelonephritis26 and renal papillary necrosis,*’ the azotemia that may occur with most NSAIDs has generally been reversible when these drugs are withdrawn.*’ Effects of NSAIDs on blood pressure and renal prostaglandin excretion29 have varied among dif- ferent observers.” Potentially, a more serious threat to patients is hyperkalemia that may develop in patients with renal insufficiency.’ In their retrospective analysis of patients at Massa- chusetts General Hospital who developed renal insufficiency during NSAID treatment, Corwin et al found an estimated overall incidence of one episode of renal dysfunction in 1,000 patient- days. Among the 26 patients who developed renal insufficiency, none had been treated with naproxen.’
The problems that may result from the drug therapy of elderly patients, ie, those aged 65 years or more, have become a major concern of all those engaged in the health care of the elderly. ‘v3i Most drugs show increases in the incidence or severity of side effects in older patients, due in large part to changes in drug pharmacokinetics that may make the elderly susceptible to drug accumulation. Older patients generally have decreased body mass and total body water. Thus, simply in terms of distribu- tion, an identical dose of a drug will produce higher plasma concentrations in an older patient than in a younger one. Furthermore, the elderly often exhibit decreases in renal function and liver blood flow and these decreases in excretion tend to further increase the concentration of a drug in the elderly as compared to younger patients. These factors are counterbalanced, to an unknown degree, by other factors that may tend
Table 5. Age Group Comparison of Values for Primary Measures of Hepatic and Renal Function and Changes
From Baseline to Last Evaluation
Baseline Mean (SEMI Change from 8aseline* Mean ISEM)
Age Group fwl Age Group hr)
Laboratory Test <65 In - 483) 265 (n - 96) <65 (n - 483) 265 (n = 96) P Valuet
*The last available laboratcq value was used for each patient, including patients who withdrew from the studies. Negative values
indicate a decrease from baseline; positive values indicate an increase. Sample sizes for individual tests differ slightly due to missing data.
TDifference betwean age groups in mean change from baseline: Wilcoxon/Mann-Whitney test.
34
to lower the plasma concentrations or area under the time-concentration curve. One of these is the generally lower concentration of serum albumin in the elderly with resultant lower capacity for protein binding, and thus, potentially, increased glomerular filtration and excretion of drugs. Additionally, drug absorption may be diminished in the elderly because of intrinsic changes in gastrointestinal function or secondary to concur- rent use of other drugs that interfere with the absorption of the drug under study. Studies to evaluate the impact of these pharmacokinetic, or other, changes in the elderly are difficult to design and interpret, in part because of the heterogeneous nature of this population (eg, numerous concomitant disease states). Pharma- cokinetics of naproxen, specifically, have been evaluated in elderly and young volunteers (Cohen et al, this supplement). Many studies of the significance of age for drug effects include only .small numbers of elderly patients and often include no younger patients for comparison.
In contrast to the expectations of increased risks associated with drug therapy in the elderly, our findings are similar to those of a retrospective analysis of 1,178 patients from nine clinical studies of naproxen which found no significant increases in the incidence of side effects in patients >65 years of age.32 Of course, in both instances, the experience in the clinical trial setting was largely with elderly patients who were selected to be relatively free of concomitant disease and concurrent drug use.
Our study specifically assessed drug effects on renal and hepatic function at conventional and high naproxen dosages. Neither symptomatic events nor any of the nine laboratory tests for renal or hepatic function showed clinically signif- icant changes in the 586 patients enrolled in these double-blind, multicenter trials. The inci- dences of clinically meaningful abnormalities of
ROBERT TURNER
laboratory data during treatment (generally 1% or less) were essentially unchanged from baseline levels. Furthermore, in the majority of patients who had such abnormalities either at baseline or during treatment, these were one-time occur- rences.
The pattern of sporadic abnormalities in labo- ratory tests, although it occurred in a small minority of patients, may have important impli- cations for patient management. The pattern indicates that occasional abnormal hepatic and renal function test results may be expected in some patients, and that these abnormal results do not necessarily warrant immediate withdrawal of naproxen treatment. The physician should evalu- ate and monitor such patients’ overall clinical condition to determine whether withdrawal of the drug should follow tests that confirm the validity of the reported abnormality.
In summary, among 586 otherwise healthy RA patients receiving 6 months of naproxen therapy at dosages of 375 mg twice daily or 750 mg twice daily, there was no laboratory or clini- cal evidence suggesting a pattern of adverse hepatic or renal effects. This was true of patients who were age 65 and older, as well as for those younger than 65 years of age. The analysis did reveal transient abnormalities of laboratory tests of hepatic and renal function among a few patients, but no indication that such abnormali- ties generally warrant immediate withdrawal of the drug. Rather, when these abnormalities appear, prudence dictates close monitoring of the patient and the use of appropriate follow-up laboratory tests to determine if continuation of treatment is warranted.
ACKNOWLEDGMENT
The author wishes to thank Laurie Peltier, Christa Basch,
Robert Wolbach, and Linda Brett for their special assistance
in preparation of this report.
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