Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose

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1 Aliment Pharmacol Ther 1999; 13: 897±906. Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose G. DOYLE, S. FUREY, R. BERLIN, S. COOPER, S. JAYAWARDENA, E. ASHRAF & L. BAIRD Clinical Research Department, Whitehall-Robins Healthcare, Madison, New Jersey, USA Accepted for publication 18 January 1998 SUMMARY Background: Delineation of non-steroidal anti-in ammatory drug (NSAID) gastrointestinal toxicity has largely depended on retrospective epidemiologic studies which demonstrate that lower doses of NSAIDs pose a lower risk of gastrointestinal toxicity. Ibuprofen, a propionic acid NSAID, has, in most such studies, exhibited a favourable pro le in terms of gastrointestinal bleeding. Since 1984, ibuprofen has been available as a non-prescription analgesic/antipyretic with a limit of 1200 mg/day for 10 days of continuous use. Trials and spontaneously reported adverse experiences suggest that gastrointestinal symptoms and bleeding are rare. Methods: This study prospectively evaluated the gastrointestinal tolerability, as compared to placebo, of the maximum non-prescription dose and duration of ibuprofen use in healthy subjects representative of a nonprescription analgesic user population. Results: Gastrointestinal adverse experiences were similar in the placebo and ibuprofen groups (67 out of 413, 16% with placebo vs. 161 out of 833, 19% with ibuprofen). There was no difference between the two groups in the proportion discontinuing due to a gastrointestinal event. Gastrointestinal adverse experiences reported by ³ 1% of subjects were: dyspepsia, abdominal pain, nausea, diarrhoea, atulence, and constipation. Seventeen (1.4%) subjects had positive occult blood tests: their frequency was comparable between treatments. Conclusions: When used as directed to treat episodic pain, non-prescription ibuprofen at the maximum dose of 1200 mg/day for 10 days, is well-tolerated. INTRODUCTION Correspondence to: Dr G. Doyle, Clinical Research Department, Whitehall- 1Robins Healthcare, 5 Giralda Farms, Madison, NJ 07940, USA. It is a generally-held view among clinicians including gastroenterologists that all NSAIDs pose a risk to the gastrointestinal tract ranging from subjective symptoms of discomfort to frank ulceration and haemorrhage. This viewpoint assumes that the nine heterogeneous classes of NSAIDs are comparable in most respects and fails to consider the pharmacological principles of dose and duration of use. NSAIDs differ widely in their pharmacological pro les. For example, half-lives vary from 2 h for ibuprofen to 50 h for piroxicam or as much as 70 h for tenoxicam. Even within an NSAID class such as the propionic acid derivatives, the potency of cyclooxygenase inhibition varies, exerting a direct impact upon the safety pro le of individual NSAIDs. Epidemiologic studies have ranked prescription ibuprofen lowest in provoking gastrointestinal bleeding or peptic ulcer compared to other prescription NSAIDs. 1, 2 Other studies have found no signi cant increase in the relative risk of gastrointestinal bleeding among ibuprofen users at a dose or duration of use beyond the US over-thecounter maximum of 1200 mg/day for 10 days. 3±9 Henry noted that the low relative risk for ibuprofen observed in studies may be re ective of the low doses Ó 1999 Blackwell Science Ltd 897

2 898 G. DOYLE et al. used as well as the short (1±2 h) half-life of ibuprofen. 10 Recent meta-analyses of 12 studies in which ibuprofen was included con rmed the observation that the lower over-the-counter analgesic doses of ibuprofen have a distinctly safer gastrointestinal pro le as compared to 11, 12 higher, prescription doses. Ibuprofen was switched from prescription to nonprescription status in the USA in 1984 based upon its ef cacy and safety pro le as a prescription drug as well as its safety pro le compared with the then-available over-the-counter analgesics, aspirin and acetaminophen. As a result of the prescription heritage of ibuprofen, adverse experience data have been mostly derived from chronic rheumatoid arthritis and osteoarthritis studies using dosage regimens in excess of those recommended on the over-the-counter label. Such studies evaluated special populations that do not represent the typical over-the-counter consumer and do not accurately re ect the true adverse experience pro le in the over-the-counter setting. Relevant published safety reports are based upon the extremes of either single-dose tolerability 13, 14 or a chronic duration of use exceeding over-the-counter labelling. 15 Recently, Strom et al. 16 examined the relative risk of gastrointestinal bleeding associated with naproxen sodium and ibuprofen using a prescription Medicaid database to approximate over-the-counter use. This analysis demonstrated, once again, an overall low incidence of upper gastrointestinal bleeding with ibuprofen at lower, overthe-counter analgesic doses. In contrast to that of the prescription-user population, the demographic pro le of the over-the-counter consumer comprises a higher proportion of younger and healthier individuals who use non-prescription analgesics intermittently to treat such self-diagnosable conditions as headache, fever, backache, dental pain, and dysmenorrhea. Because there are no published data on the gastrointestinal effects of ibuprofen when directly tested at the maximum over-the-counter dose in the USA, of 1200 mg for 10 consecutive days, this study was designed to examine this aspect of its safety pro le in two formulationsðliquigel and tablet. Subjects were enrolled across a wide age range to approximate the typical over-the-counter analgesic user population. The population was `all comers' with a few exceptions related to direct NSAID contraindications. Stool occult blood tests were obtained from subjects twice during dosing to determine whether ibuprofen could induce clinically inapparent gastrointestinal bleeding. MATERIALS AND METHODS Study design This multiple-dose, double-blind, randomized, age-strati ed, placebo-controlled, parallel group, out-patient study was conducted at six study sites. Eligible participants were randomly assigned according to a computer-generated code in a 2 : 2 : 1 : 1 ratio to: ibuprofen liquigel capsule 200 mg, ibuprofen tablet 200 mg, liquigel capsule placebo, and tablet placebo, respectively. Each study site was randomized independently, and within each site, subjects were strati ed into one of three age categories demographically representative of the over-the-counter analgesic user population: 12±34, 35±64, 65 + years. 17 Subjects provided a brief medical history, including information regarding their past use of analgesics. Eligible subjects were given study medication and instructed to take two 200 mg capsules (or tablets) every 4±6 h for a total of six capsules or tablets per day for 10 consecutive days. Since the study was doubleblind, subjects were provided with acetaminophen in case they required an analgesic. On days 7 ( 1 day) and 10 ( 1 day), subjects collected faecal samples for subsequent occult blood testing (Hemoccult slides; SmithKline Laboratories). Subjects were instructed to follow the directions for stool collection and storage on the envelope containing the slides. Subjects returned the Hemoccult slides to the study site within 1 week of completing the 10-day evaluation. At the return visit, the Hemoccult slides were processed. If one or both of the slides were positive, the subject was referred to a physician (personal or referral). Subjects Eligible subjects were at least 12 years of age and were regular consumers of over-the-counter analgesics (i.e. had a history of over-the-counter analgesic use of at least three but no more than nine times per month for the past 3 months); and all women were using a reliable method of contraception. The study excluded individuals who had any serious medical condition or used prescription drugs(s) with which NSAID administration was speci cally contraindicated; had a known sensitivity to ibuprofen, or any other NSAID; had taken an investigational drug within the past 30 days; were pregnant or nursing. All subjects provided written informed consent on a

3 GASTROINTESTINAL SAFETY OF OTC IBUPROFEN 899 form approved by a certi ed Institutional Review Board. Safety evaluation Each day that study medication was taken, the subjects answered the following question in their diary: `Have you experienced any medical problems or symptoms today?' Subjects then recorded a description of the condition, severity, and onset of the problem or symptom. In addition, subjects were contacted on study days 2, 6, and 9 to review study procedures and answer questions. Upon returning to the clinic, additional details about any adverse experiences were obtained from the subject. The investigator then assessed the time of onset, offset, severity, drug relatedness, action taken, outcome, and whether or not the adverse experience was present pre-study. Subjects were provided with an envelope containing two slides for occult blood testing and were directed to collect their stool on days 7 and 10 of dosing. Statistical analysis All subjects who took study medication and returned a diary were included in the analysis. Adverse experiences were classi ed according to the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) dictionary, third edition. Each term was classi ed by body system according to the same dictionary, except for the COSTART terms `abdominal pain' and `dry mouth', which were reassigned to the Digestive System. Differences among and between means and proportions were declared statistically signi cant if the probability of random occurrence was P All statistical tests were performed using SAS version 6. Continuous demographic variables were analysed using analysis of variance with effects for treatment, site, and their interaction. Categorical demographic variables were analysed using the Cochran±Mantel±Haenszel test, controlling for site. Fisher's exact test was used to assess the comparability of the treatment groups with respect to: the frequency of adverse experiences (all reported events regardless of drug relationship were included in the analysis); the proportion of subjects who discontinued from the study due to adverse experiences; and the proportion of subjects with positive faecal occult blood tests on days 7, 10, and both days. The 95% exact con dence bounds for the odds ratio for the incidence of an adverse experience with ibuprofen compared to placebo are also presented. Prospectively, a sample size of» 400 subjects in each of the active treatment groups was selected to provide a 90% statistical power to detect a 9% excess in the incidence of gastrointestinal adverse experiences for ibuprofen liquigel relative to ibuprofen tablets. RESULTS Subjects There were 1257 subjects randomized to treatment with placebo (liquigel or tablet), ibuprofen liquigel, and ibuprofen tablet. Eleven subjects left the study prior to taking any study medication. The remaining 1246 subjects were included in the primary analysis: 413 placebo; 833 ibuprofen (n ˆ 418 liquigel, n ˆ 415 tablet). Compliance, i.e. ingestion of all 60 tablets/ capsules, was 93%. A total of 1206 subjects (96%) completed the entire 10-day treatment period. Baseline demographics, incidence of gastrointestinal events, and guaiac test results were found to be comparable between both placebo groups as well as between ibuprofen tablet and liquigel groups. Based upon the foregoing results, as well as the proven comparable bioavailability (AUC) of the ibuprofen liquigel and tablet formulations, data for both ibuprofen formulations were pooled for analysis as were data from the two placebo groups. For comparative purposes the results are tabulated for each formulation, however, only the combined ibuprofen treatment groups are discussed. Given the observed placebo rate of gastrointestinal adverse events (16.2%), this study had a 95% power to detect a 9% higher gastrointestinal event rate in the ibuprofen group compared to the placebo group (at 5% signi cance level). The treatment groups were comparable for demographic pro le (Table 1), medical history, and history of past analgesic use. Approximately half of each treatment group reported using an over-the-counter NSAID, while one-third used acetaminophen exclusively. Fifteen subjects discontinued due to adverse effects: ve taking placebo (1.2%) and 10 taking ibuprofen (1.2%). Of these, two in the placebo group (0.5%) and four in the ibuprofen group (0.5%) discontinued due to gastrointestinal adverse effects. Four subjects experienced serious adverse effects (non drug-related) requiring hospitalization: three participants were taking ibuprofen

4 900 G. DOYLE et al. Table 1. Demographic pro le of subjects Total (n = 1246) PBO (n = 413) IBU (n = 833) P-value* LIQ (n = 418) TAB (n = 415) Sex (%) F/M 54/46 56/44 53/ /48 54/46 Race Black 12% 12% 11% % 10% Caucasian 85% 84% 85% 84% 87% Hispanic 3% 4% 3% 3% 3% Other 0% 0% 1% 1% 0% Mean Age (Range) 44.2 (12±83) 44.4 (12±80) 44.1 (13±83) (13±82) 43.9 (13±83) s.d Mean Wt (Range) (84±360) (84±335) (92±360) (102±343) (92±360) s.d * IBU compared to placebo. PBO = placebo; IBU = combined ibuprofen treatment groups, LIQ = liquigel, TAB = tablet, n = number of subjects. (accidental baclofen overdose, alcohol withdrawal syndrome, acute diverticulitis) and one was taking placebo (acute gangrenous cholecystitis). Adverse experiences Overall, 47% of the subjects reported at least one adverse experience. A signi cantly greater percentage of placebo subjects (53%) reported an adverse experience, as compared to the ibuprofen subjects (44%) (Table 2). Placebo-treated and ibuprofen-treated subjects had a similar incidence of gastrointestinal adverse effects (67 out of 413, 16% and 161 out of 833, 19%, respectively; P-value ˆ 0.187, odds ratio (OR) ˆ 1.24, 95% CI: 0.90±1.72). Gastrointestinal adverse effects reported by at least 1% of the subjects are shown in Table 2. Gastrointestinal adverse effects reported by both treatment groups were predominantly mild or moderate. The most frequently reported non-gastrointestinal adverse effects were classi ed to the Body as a Whole (headache, pain/back pain, and cold) and were Table 2. Adverse effects classi ed by organ system PBO (n = 413) IBU (n = 833) Odds Ratio LIQ (n = 418) TAB (n = 415) Organ system # Subj (%) # Subj (%) (95%C.L.) P-value # Subj (%) # Subj (%) Any Body System 217 (52.5) 366 (43.9) 0.71 (0.55±0.90) 0.005* 185 (44.3) 181 (43.6) Body as a Whole 172 (41.6) 238 (28.6) 0.56 (0.43±0.72) < 0.001* 119 (28.5) 119 (28.7) Gastrointestinal 67 (16.2) 161 (19.3) 1.24 (0.90±1.72) (20.3) 76 (18.3) Dyspepsia 23 (5.6) 62 (7.4) 1.36 (0.82±2.34) (7.9) 29 (7.0) Abdominal pain 14 (3.4) 36 (4.3) 1.29 (0.67±2.61) (5.0) 15 (3.6) Nausea 13 (3.1) 30 (3.6) 1.15 (0.57±2.43) (3.6) 15 (3.6) Diarrhoea 16 (3.9) 23 (2.8) 0.70 (0.35±1.44) (2.6) 12 (2.9) Flatulence 8 (1.9) 17 (2.0) 1.05 (0.43±2.85) (2.2) 8 (1.9) Constipation 8 (1.9) 16 (1.9) 0.99 (0.40±2.70) (1.9) 8 (1.9) Respiratory 27 (6.5) 49 (5.9) 0.89 (0.54±1.51) (6.2) 23 (5.5) Nervous 13 (3.1) 29 (3.5) 1.11 (0.55±2.35) (2.6) 18 (4.3) Musculoskeletal 12 (2.9) 16 (1.9) 0.65 (0.29±1.53) (2.2) 7 (1.7) Special senses 5 (1.2) 13 (1.6) 1.29 (0.43±4.67) (1.9) 5 (1.2) Urogenital 6 (1.5) 8 (1.0) 0.66 (0.20±2.32) (0.7) 5 (1.2) Skin 5 (1.2) 5 (0.6) 0.49 (0.11±2.16) (0.2) 4 (1.0) Metabolic/nutritional 1 (0.2) 8 (1.0) 4.00 (0.53±177.70) (0.5) 6 (1.4) Cardiovascular 1 (0.2) 3 (0.4) 1.49 (0.12±78.36) (0.0) 3 (0.7) Hemic/lymphatic 1 (0.2) 0 (0.0) (0.0) 0 (0.0) IBU compared to PBO; * statistically signi cant at P PBO = placebo; IBU = combined ibuprofen treatment groups; LIQ = liquigel; TAB = tablet.

5 GASTROINTESTINAL SAFETY OF OTC IBUPROFEN 901 signi cantly lower among those taking ibuprofen, compared to placebo-treated subjects (Table 2). Subjects with a positive gastrointestinal history were not excluded. Two-placebo treated subjects and four ibuprofen-treated subjects were receiving a concomitant H 2 antagonist, proton pump inhibitor, or antacid during the trial. None of these subjects developed gastrointestinal adverse effects. Nineteen placebo-treated and 48 ibuprofen-treated subjects reported a history of ongoing upper gastrointestinal symptoms such as indigestion/ dyspepsia, or heartburn at screening. Of this group, details on the ve placebo-treated and 14 ibuprofentreated subjects who reported gastrointestinal symptoms during the trial are shown in Table 3. In all cases, the severity ranged from mild to moderate and resolved either spontaneously or with non-prescription H 2 antagonists or antacids. None of the subjects left the study. Analysis of adverse effects by age The overall adverse effect frequency was comparable between ibuprofen-treated and placebo-treated subjects in the 35±64 and ³ 65 years age groups. In the 12± 34 years age group, a signi cantly (P ˆ 0.001) higher percentage of placebo subjects (61%) reported an adverse effect than did ibuprofen subjects (43%, OR ˆ 0.48, 95% CI: 0.30±0.75); this was largely due to the higher percentage of Body as a Whole adverse effects among placebo-treated subjects (52%) compared to ibuprofen-treated subjects (32%). In the 35±64 years age group, the frequency of dyspepsia was greater among ibuprofen-treated subjects (8.9%) compared to placebo (3.3%, P ˆ 0.012, OR ˆ 2.80, 95% CI: 1.20±7.57). Within each age stratum, the incidence of positive occult blood tests was 2%, and both treatments within each age group were comparable in the frequency of positive tests. Analysis of adverse effects by gender Signi cantly more placebo-treated men (51%) reported an adverse effect than did ibuprofen-treated men (34%, P < 0.001; OR ˆ 0.50, 95% CI: 0.34±0.73). The overall incidence of gastrointestinal adverse effects (placebo ˆ 14%, ibuprofen ˆ 13%, P ˆ 0.596) and the incidence of speci c gastrointestinal adverse effects was not signi cantly different between the placebo and ibuprofen -treated men (OR ˆ 0.86, 95% CI: 0.50±1.5). The overall incidence of adverse effects reported by placebo and ibuprofen-treated women was similar (54% and 53%, respectively, P ˆ 0.807; OR ˆ 0.95, 95% CI: 0.68±1.32). Signi cantly more placebo-treated women reported pain and back pain (9.1% and 6.1%, respectively) compared to ibuprofen-treated women (3.8% and 2.5%, respectively; P ˆ 0.008, OR ˆ 0.40, 95% CI: 0.19±0.81 and P ˆ 0.03, OR ˆ 0.39, 95% CI: 0.16± 0.96, respectively). The frequency of gastrointestinal adverse effects was higher in ibuprofen-treated women (25%) than among placebo-treated women (18%; P ˆ 0.03; OR ˆ 1.57, 95% CI: 1.04±2.4). There were no signi cant differences between groups for any speci c gastrointestinal adverse effect. For both men and women, the frequency of positive stool occult blood tests was comparable between those receiving ibuprofen and those receiving placebo. The frequency of dyspepsia among subjects who used acetaminophen as their predominant over-the-counter analgesic (placebo ˆ 124 subjects, ibuprofen ˆ 231 subjects) was similar between treatment groups (placebo ˆ 2.4%, ibuprofen 4.6%, P ˆ 0.395, OR ˆ 2.017, 95% CI: 0.518±11.45). Faecal occult blood Seventeen of 1216 subjects (1.4%) with valid tests had at least one positive faecal occult blood test. The rate was comparable between the treatment groups on day 7, day 10, and overall. Only four of 1196 subjects (0.3%) had positive results on both days 7 and 10. Of the 17 subjects with positive tests for stool occult blood (Table 4), ve had an underlying non-drugrelated gastrointestinal condition (e.g. haemorrhoids). Of the remaining 12 subjects, nine agreed to receive medical follow-up care which determined no gastrointestinal pathology or aetiology for the positive test results (three subjects declined to seek follow-up care). The frequency of positive occult blood tests not attributable to an underlying condition (0.8%) was consistent with the known false positive rate (2%) of the faecal occult blood test. 18 Since subjects were not required to follow the manufacturer's instructions for testing, false positives were not unexpected. The comparably low overall incidence of gastrointestinal bleeding associated with the administration of ibuprofen in this trial is consistent with the epidemiological literature for the

6 Table 3. Subjects with positive upper gastrointestinal symptoms at baseline who experienced gastrointestinal symptoms during trial Subject No./ GI symptom(s) GI symptom(s) No. tablets/capsules Resolution/ Age/Sex at baseline during trial ingested prior to AE Worst severity treatment 902 G. DOYLE et al. Ibuprofen (n = 14) /F Indigestion Gastric distress 38 Moderate Spontaneously /F Dyspepsia Dyspepsia 52 Moderate Non-prescription H 2 antagonist /F Indigestion Dyspepsia 20 Moderate Non-prescription H 2 antagonist /F Indigestion Indigestion 28 Moderate Antacid /F Indigestion Indigestion 4 and 24 Moderate Non-prescription H 2 antagonist /F Indigestion Nausea, abdominal pain, 8, 10, 44 Moderate Spontaneously or antacid dyspepsia respectively /M Chr abdominal pain, Indigestion 26 Mild Non-prescription H 2 antagonist nausea, indigestion /M Oesophageal re ux, Dyspepsia 18 Moderate Antacid indigestion /F Dyspepsia Dyspepsia 20 Mild Spontaneously /M Indigestion Nausea, 54 Moderate Spontaneously abdominal pain /M Indigestion Heartburn 12 Mild Antacid /M Heartburn Hearburn 44 Moderate Spontaneously or nonprescription H 2 antagonist /F Indigestion Indigestion 10, 26 Moderate Spontaneously /M Dyspepsia Dyspepsia 2 Mild Non-prescription H 2 antagonist Placebo (n = 5) /F Indigestion Dyspepsia 26 Mild Spontaneously /F Indigestion Dyspepsia 26 Mild Antacid /F Indigestion Indigestion 50 Mild Antacid /M Indigestion Hyperacidity 42 Moderate Non-prescription H 2 antagonist /F Indigestion Heartburn 30, 32 Moderate Spontaneously GI = Gastrointestinal; AE = adverse effect.

7 Table 4. Subjects with positive haemoccult tests Subject Age/sex Concomitant drugs Day 7/10 Follow-up procedure Diagnoses Gastrointestinal adverse effects Placebo /F oestrogen )/+ repeat Hemoccult negative diarrhoea /F benzamycin, vitamins )/+ sigmoidoscopy negative none /F none )/+ endoscopy negative none /F oestrogen + medroxyprogesterone +/+ repeat Hemoccult negative indigestion Ibuprofen /F vitamins )/+ repeat Hemoccult negative none /F none )/+ repeat Hemoccult negative none /M vitamins, herbal preparation +/+ repeat Hemoccult bleeding haemorrhoids constipation, bleeding haemorrhoids /M diltiazem )/+ colonoscopy acute diverticulitis, colonic polyps, acute diverticulitis, colonic polyps, colonic ulceration colonic ulceration /M none +/) none ± subject refused negative none /F oestrogen, medroxy-progesterone +/) endoscopy negative none /M B-carotene, vitamin C, soya lecithen +/) sigmoidoscopy haemorrhoids, rectal polyps haemorrhoids, rectal polyps /F estradiol, uoxetine, vitamins )/+ sigmoidoscopy diverticulosis diverticulosis /F none +/) none ± subject refused negative none /M none )/+ repeat Hemoccult negative none /M vitamins +/+ repeat Hemoccult negative none /M none +/) none ± subject refused negative none /M none +/+ colonoscopy, upper GI series haemorrhoids, hiatal hernia haemorrhoids All subjects took entire course of treatment (i.e. 60 tablets/capsules) except #'s 3206 and 3264 who took 58 tablets/capsules. GASTROINTESTINAL SAFETY OF OTC IBUPROFEN 903

8 904 G. DOYLE et al. administration of over-the-counter doses of ibuprofen. 2, 3, 6, 19 DISCUSSION This study was the rst to examine the gastrointestinal tolerability of the maximum labelled daily dose of overthe-counter ibuprofen (1200 mg) for 10 consecutive days among typical users of over-the-counter analgesics. The results of this placebo-controlled trial are consistent with previously published studies indicating that the potential for ibuprofen to provoke gastrointestinal irritation is low in a typical over-the-counter-user population, including individuals who predominantly use acetaminophen as their over-the-counter analgesic. Results from within each of the three age groups (12± 34 years, 35±64 years, and ³ 65 years) were generally consistent with those from the entire sample population. The clinical signi cance of a higher dyspepsia rate among those 35±64 years of age who received ibuprofen is questionable for two reasons: (i) there was no corresponding difference within this strata for other closely related upper gastrointestinal symptoms such as nausea and abdominal pain; and (ii) this nding was not replicated in either of the other two age strata. Additionally, 11 of the 37 cases of dyspepsia in the ibuprofen group were present at baseline compared to zero out of seven in the placebo group. Among subjects 35±64 years of age there was a difference between treatment groups at screening with respect to the presence of upper gastrointestinal symptoms (dyspepsia, heartburn, indigestion). A comparison of treatmentemergent upper gastrointestinal symptoms was conducted to take into account this baseline difference. The incidence of an upper gastrointestinal event in this age group is 3.52% and 6.63% for placebo and ibuprofen, respectively, which is not a signi cant difference (P ˆ 0.133, OR ˆ 1.95, 95% CI: 0.80±5.4). Signi cantly more women in the ibuprofen group (25%) than in the placebo group (18%) reported gastrointestinal adverse effects; however, there were no signi cant differences between the treatment groups for any individual gastrointestinal adverse effects and no trend effect in any age strata. Since the frequency of gastrointestinal adverse effects was similar for placebo and ibuprofen in the overall population, this nding was deemed to be clinically unimportant. The tolerability of ibuprofen at the maximum over-thecounter dosage was further demonstrated by the low percentage of subjects who discontinued due to adverse effects (1.2% in both the ibuprofen and placebo treatment groups). This low percentage compares favourably with other multiple-dose studies that have evaluated chronic ibuprofen therapy at higher prescription dosages of up to 3200 mg/day. 20, 21 Additionally, the ndings of this study are consistent with the results from previous analyses of single/ multiple dose over-the-counter studies. 13, 14 Furey reported the side-effects from 15 double-blind randomized controlled trials of over-the-counter doses of ibuprofen, acetaminophen, and placebo. 13 A total of 878 subjects received ibuprofen 200 or 400 mg, 849 acetaminophen 650 or 1000 mg, and 852 placebo. The overall frequency of side-effects was comparable; ibuprofen 2.4%, acetaminophen 3.2%, and placebo 2.1%. Upper gastrointestinal upset ranged from 0.8 to 0.9% of subjects in all groups. In DeArmond et al.'s. 14 review of 19 studies utilizing single or multiple over-the-counter doses of ibuprofen as the active comparator, a total of 1574 patients received single or multiple doses of ibuprofen 200 or 400 mg and 1061 received placebo. The proportion of subjects who reported adverse effects was similar in the ibuprofen and placebo groups (12.3% and 13.4%, respectively). The most common gastrointestinal adverse effect was nausea reported by 2.1% of placebo-treated subjects and 2.2% of subjects in the ibuprofen group. The observations in the subset of subjects who reported an ongoing history of upper gastrointestinal symptoms at trial entry are clinically relevant because they dispel the notion that use of even an over-the-counter dose of an NSAID will invariably lead to exacerbated gastrointestinal symptoms. Overall, adverse effects were reported by a total of 47% of subjects (53% in the placebo group, and 44% in the combined ibuprofen group). In addition to the speci c prompting for adverse effects, this high frequency was directly related to the high incidence (33%) of Body as a Whole adverse effects, such as headache, backache, u, and cold. One could expect that during a 10-day period,» 50% of study subjects would report one or more miscellaneous and probably non-drug related event. Of interest, the proportion of subjects in the ibuprofen group who reported any adverse effects was signi cantly lower than in placebo-treated subjects. This nding could be attributed to the treatment/ prevention of painful symptoms by ibuprofen and all subjects' avoidance of other analgesic use for a

9 GASTROINTESTINAL SAFETY OF OTC IBUPROFEN 905 continuous 10-day period. A statistically signi cantly greater number of placebo-treated subjects (n ˆ 139) took at least one dose of supplementary medication than either of the ibuprofen treatment groups (liquigel ˆ 92, tablet ˆ 81). Subjects in this trial were required to provide stool samples on study days 7 and 10 for occult blood testing. The reported speci city of the test used in this trial is 98%, 18 with the overall frequency of positive results ranging from 1.1% to 7.7% in uncontrolled trials and 1.0% to 3.7% in controlled trials. 22 In the present study, the rate of positive tests was 1.4% and there was no signi cant difference between the treatment groups for the proportion of subjects with a positive result. Of the 17 subjects with positive occult blood tests, ve were diagnosed with an underlying pathology unrelated to study medication that reasonably explained the positive result and three refused follow-up care. The remaining nine subjects who had negative follow-up may have had positive stool guaiac tests during the study due to variances in dietary intake, false positives, or drug use. No subjects were rechallenged with drug. Despite the non-speci city of positive guaiac tests, they are an indirect measure of gastrointestinal bleeding. The high compliance rate of 96% of subjects submitting faecal samples indicates that the procedure can be readily incorporated to large prospective studies. The results demonstrate that the maximum labelled dosage of over-the-counter ibuprofen is not associated with occult gastrointestinal blood loss into the gastrointestinal tract above the background frequency reported for placebo. In this large prospective study, there was no evidence of increased gastrointestinal bleeding as measured by guaiac test performed on two days, nor was there any evidence in the overall population of a substantial difference in subjective symptoms. 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