The long-term safety and established efficacy of proton ORIGINAL ARTICLES

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2:17 21 ORIGINAL ARTICLES Self-Selection and Use Patterns of Over-the-Counter Omeprazole for Frequent Heartburn A. MARK FENDRICK,*, MICHAEL SHAW, BERNARD SCHACHTEL, LISA ALLGOOD, GREG ALLGOOD, JULIE GRENDER, and DAVID PEURA # Departments of *Internal Medicine and Health Management and Policy, University of Michigan, Ann Arbor, Michigan; Park Nicollet Health System, Minneapolis, Minnesota; Schachtel Research, Jupiter, Florida; Procter & Gamble Health Sciences Institute, Cincinnati, Ohio; and # Department of Internal Medicine, University of Virginia, Charlottesville, Virginia Background & Aims: The Food and Drug Administration approval and subsequent launch of over-the-counter (OTC) omeprazole raises the question whether consumers would use OTC omeprazole appropriately in a real world setting. Methods: A3-month observational study was conducted in an OTC setting to determine whether consumers could (1) correctly self-select to use omeprazole for frequent heartburn, (2) comply with a product label that calls for 14 consecutive days of once-daily dosing, and (3) use more than 14 doses of medication only under the advice of a physician. Consumers were interviewed at 5 shopping malls in geographically distinct areas of the United States and asked whether they had heartburn. Of the 1999 self-reported heartburn sufferers, 866 determined the product was appropriate for their condition and purchased the product; of these, 758 (88%) returned diaries documenting product usage and physician contact. Results: OTC consumers accurately self-selected; more than 90% of participants had heartburn 2 or more days/week. Analysis of diary data showed a high degree of compliance to label use directions; only 3% of subjects took more than 14 doses without consulting a physician. After 3 months, 43% of subjects did not have recurrence of heartburn. Overall, 75% of subjects had contact with a physician about heartburn before, during, or soon after the study (26% contacted a physician during the 3-month study). Of the 758 subjects, only 1 subject took more than 14 tablets without consulting a physician and had recurrence of heartburn. Conclusions: Actual use data support that consumers accurately self-select if an OTC proton pump inhibitor is appropriate for use, comply with a 14-day regimen in the OTC setting, and appropriately seek physician involvement for longer-term management of frequent heartburn. The long-term safety and established efficacy of proton pump inhibitors led the Food and Drug Administration (FDA) to approve omeprazole for over-thecounter (OTC) use in the summer of Although OTC omeprazole was made available for purchase in September of that same year, it had not been established whether consumers would use OTC omeprazole appropriately in a real world setting. Specific concerns about OTC switches include inappropriate self-selection, incorrect dosing and treatment duration, as well as fears that unsupervised use might delay physician contact and mask serious conditions. To address these issues, a 3-month observational study was designed to investigate how consumers select and use omeprazole under naturalistic conditions. Specific aims were to determine appropriate self-selection as described on the product label, describe compliance with a label that calls for a 14-day regimen, measure physician contact for heartburn, and assess heartburn symptoms and associated medication use for heartburn after the trial period. Methods Study Design and Sample Recruitment A multi-site, open-label, actual use study was undertaken to assess how consumers select, use, and respond to OTC omeprazole. Consumers were approached at a kiosk in a shopping mall in 5 cities in the Northeast, Southeast, Midwest, and Southwest regions of the United States and queried whether they had heartburn. Study personnel (who were not in the healthcare field) were explicitly instructed not to use any cues (e.g., age, gender, body size) to aid in the selection of potential study candidates. Consumers who self-reported to have heartburn were invited to participate in the study. Heartburn was Abbreviations used in this paper: FDA, Food and Drug Administration; H 2 RA, histamine-2 receptor antagonist; OTC, over-the-counter by the American Gastroenterological Association /04/$30.00 PII: /S (03)

2 18 FENDRICK ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 1 not further defined or characterized except on the product label. Demographic information and data regarding health insurance status, heartburn history, heartburn medication use, and physician contact for heartburn were collected from willing participants. Each potential consumer was then shown the OTC omeprazole carton, and, only on the basis of their understanding of the carton label, they determined whether the medication was appropriate for them to use. Lay study personnel did not tell consumers any information about the drug, other medications they might or might not take, or other details that might influence behavior. Those who believed that OTC omeprazole was an appropriate treatment option were offered an opportunity to purchase the product at the intended market price. Once a consumer purchased the study drug, a diary was provided to measure patterns of OTC omeprazole use during the 3-month study period. Consumers were free to purchase multiple cartons at the initial visit and could return to the mall kiosk to purchase additional cartons during an additional 8 weeks. Three months after study initiation (4 weeks after the last opportunity to purchase), each subject was contacted by telephone for an interview to assess heartburn symptoms and related treatment. No visits or telephone calls with consumers were scheduled between the initial visit and the follow-up telephone interview. Outcomes Measured Self-selection. Appropriate self-selection was determined as meeting 6 specific criteria as noted on the OTC omeprazole product label. Individual criteria included heartburn symptoms 2 or more days/week; 18 years of age or older; not pregnant/lactating; not allergic to omeprazole; no contraindicated symptoms that were not reported to a healthcare provider (frequent chest pain; chest pain with shortness of breath; sweating; pain spreading to arms, neck, or shoulders; or lightheadedness; trouble swallowing food; frequent wheezing, particularly with heartburn; and unexplained weight loss); and not taking contraindicated medications (phenytoin, diazepam, warfarin, clarithromycin, itraconazole, ketoconazole) without notification to a healthcare provider. Compliance and duration of use. OTC omeprazole use patterns were determined from the subject diaries. Compliance with the 14-day, one pill daily, dosing regimen as described in the product label was predefined as taking doses of medication during an 11- to 17-day period. If a subject took more than 14 doses, a consultation with a healthcare provider was required to be considered compliant. Physician contact and heartburn medication use. Physician contact for heartburn was assessed before, during, and immediately after the trial. Heartburn medication use, in the presence or absence of frequent heartburn recurrence, was assessed at study entry and at the 3-month follow-up interview. Results Study Sample At the 5 shopping mall kiosks, 1999 individuals self-reported to have heartburn. Of these, 1300 consumers completed an initial interview during which data regarding health insurance status, heartburn history, heartburn medication use, and physician contact for heartburn were collected. Of those interviewed, 866 individuals stated that they could use and were willing to purchase OTC omeprazole ( self-selected population ). Reasons for nonparticipation included (1) study participation would be inconvenient (115, 30%), not willing to try new medications without physician approval (104, 27%), happy with current medication (32, 8%), product was too expensive (19, 5%), do not use medication (5, 1%), and other (109, 29%). Twelve potential purchasers of OTC omeprazole were not permitted to purchase product; 4 had participated in a previous omeprazole trial, 4 withdrew informed consent, 3 were younger than 18 years of age, and 1 was pregnant. Of the 854 diaries distributed to purchasers of study medication who signed informed consent, 758 (89%) were returned. Demographic characteristics and clinical information regarding heartburn of this actual use population (n 758) and those individuals who had self-responded to the heartburn question but did not agree to participate in the study (n 384) are shown in Table 1. Appropriate Self-Selection Of the 866 self-selected purchasers of OTC omeprazole, 81% met all 6 prespecified criteria required for appropriate self-selection. For each individual criterion, 90% 100% of the subjects correctly determined the appropriate study medication. Frequent heartburn. Ninety percent of subjects reported a history of frequent heartburn (2 or more days per week). Of those with infrequent heartburn who took study medication, none took more than 14 tablets. Eighteen years of age or older. All but 3 purchasers were 18 years of age or older. Not pregnant or nursing. Only 1 of the 507 women who attempted to enter the trial was pregnant. She had a history of taking omeprazole, a current prescription for another proton pump inhibitor, and was under evaluation by her doctor for unexplained nausea. Not allergic to omeprazole. No subjects were allergic to omeprazole. No contraindicated symptoms. Of the self-selection population of 866, 82 (9.5%) reported a history of experiencing 1 or more contraindicated symptoms without having previously consulted a doctor about that

3 January 2004 SELF-SELECTION AND USE PATTERNS OF OTC OMEPRAZOLE 19 Table 1. Study Population Subjects who used study medication and returned use diary (N 758) Consumers with heartburn who did not purchase product (N 384) Female 59% 61% Race Black 14% 23% White 70% 59% Hispanic 10% 11% Other 6% 7% Age (mean) 49 yr 46 yr Highest education level Some high school or 6% 9% less High school diploma or 25% 32% GED Some college 41% 34% College degree or 28% 36% more Heartburn duration 1 yr 9% 12% 1 5 yr 45% 43% 5 yr 46% 46% Heartburn frequency Heartburn 2 days/wk 9% 23% Heartburn 2 days/wk 91% 77% Previous OTC 91% 88% heartburn medication (yes) Health insurance (yes) 87% 82% symptom. No subject in this group who used study medication (n 63) took more than 14 tablets. In addition, two thirds of these subjects did consult with a physician about their heartburn before, during, or soon after the trial, and 6 of 63 subjects (10%) consulted with a physician about their heartburn for the first time. Contraindicated medications. Fifteen subjects reported taking 1 of the 6 contraindicated medications as listed on the product label; 13 (87%) consulted a physician about their heartburn during or soon after the trial. Two subjects reported taking phenytoin (Dilantin) on their medication history, yet they answered no when asked if they took phenytoin, suggesting they did not recognize the generic name. Six subjects reported taking diazepam during the study, 3 of whom (50%) were under the care of a physician; 1 received a single dose of diazepam preoperatively during the trial, and the other 2 had concurrent prescriptions for a proton pump inhibitor. Six subjects took warfarin during the trial. Of these, all 6 subjects contacted a physician during or after the study; 4 (67%) subjects had consulted their physician during the study period and were told to continue taking omeprazole with warfarin. One subject noticed the warning after 2 doses, stopped taking omeprazole, and contacted her physician. The final subject had a scheduled appointment with her physician after study completion to discuss heartburn. One subject was prescribed clarithromycin for a sinus infection during the study, and this subject informed the physician that he was taking omeprazole. Compliance with OTC Omeprazole Label Overall, 79% of the actual use population were compliant with the label within protocol specifications (11 14 doses within days) or had consulted with a physician about heartburn if they took more than 14 doses. Dosing patterns different than above included 9% who took fewer than 11 doses; less than 1% who took doses during fewer than 11 days; and 9% who took doses in more than 17 days. Of the 34 subjects who took more than 14 doses, 14 (41%) contacted a healthcare provider during the study, and 29 (85%) had contacted a healthcare provider for heartburn before, during, or soon after the study. Ninety-eight percent of all dosing days involved only 1 tablet, and 91% of all subjects took no more than 1 tablet per day. Ninety-six percent of subjects used only 1 carton (14 tablets or less) during the trial, 2% used 2 cartons, 1% used 3 cartons, and 1% used 4 cartons. Return of Frequent Heartburn and Subsequent Management Of the 758 subjects who returned a diary, 649 (86%) were successfully contacted by telephone call to assess whether frequent heartburn had recurred and related treatment. Three months after the study initiation (and approximately 10 weeks after OTC omeprazole therapy for the 95% of consumers who purchased only 1 carton), 43% stated that their frequent heartburn had not returned. Just more than half (57%) of those subjects who returned a diary reported recurrent heartburn. This rate of remission is consistent with reports in the literature for patients with gastroesophageal reflux disease after a 14- to 28-day course of therapy with omeprazole 20 mg. 1,2 A great majority (86%) of those with recurrent symptoms reported using medications to treat their symptoms; 39% used antacids alone, 16% used OTC histamine-2 receptor antagonists (H 2 RAs), 5% used both, and 26% reported using prescription antisecretory medications. Physician Contact Contact with a healthcare provider regarding heartburn was assessed before the study, throughout the study, and at the follow-up interview. Overall, 565 (75%) of purchasers who returned a diary had physician

4 20 FENDRICK ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 1 Figure 1. Physician contact for heartburn. contact about their heartburn before, during, or soon after the trial (Figure 1). One hundred nineteen (16%) contacted a physician during the 2-month study; 78 (10%) additional subjects contacted their provider between the end of the study and the 3-month follow-up interview. Another 58 (8%) reported scheduling an appointment to see their doctor about heartburn soon after the study. In addition, 237 (31%) subjects had consulted their doctor or had a prescription for heartburn within the past year, and an additional 73 (10%) subjects consulted their doctor or had a prescription for heartburn more than a year ago. Of the 758 subjects who returned a diary, 265 (35%) stated that they had never consulted a doctor about their heartburn before the study. Of these 265 OTC omeprazole users, 54 (20%) consulted a doctor about their heartburn for the first time in association with the study. Of the 37 subjects who took study medication, reported a contraindicated symptom, and had never consulted a physician about heartburn or the contraindication, 6 (16%) did so for the first time during or soon after the study. The percentage of subjects who consulted a physician during the study increased to 41% among those who took greater than 14 doses compared to 21% for all subjects who took study medication. Subjects who exceeded 14 doses of therapy had the highest physician consultation rate (86%) of any subgroup in the study. Discussion Actual use studies are playing an increasingly important role for prescription pharmaceuticals being considered for a switch to OTC status. By examining several indicators of consumer behavior, these observational studies can provide consumer advocates and regulatory officials with evidence of what is actually going to happen if the proposed OTC drug becomes available. This actual use study of OTC omeprazole used a naturalistic study design to document consumers use of an OTC drug under free-living conditions. The subjects in this study were actual consumers whose enrollment was entirely contingent on their independent decision to purchase the study drug on the basis of the information provided on the package label. Another feature of this actual-use study design that reproduced the real behavior of consumers was the decision-to-purchase criterion. After consumers indicated that they considered the drug appropriate for their heartburn, they were asked whether they wanted to buy the product at intended market price. In contrast with other actual-use studies in which the test product is offered to consumers at no cost, consumers in this study paid for it. To provide the customary conditions of purchase in a realistic setting of OTC drug utilization, repurchasing was available at the mall kiosks for an additional 8 weeks. We thus assured that overpurchasing could occur during a time period that extended 4-fold beyond the labeled duration of use (a time period when relapse of heartburn could also be expected to return). This feature of the study design also provided an opportunity to observe compliance with the 14-day limitation of use on the label. Like all cohort studies, this study is limited by the possibility that the recruited sample might not be representative of the general population. Because the aims/ design of this trial were to mimic the real world as closely as possible, we tried to minimize selection bias in the selection of our sites, the use of nonmedical interviewers, and the requirement of purchase to enroll. The study design implemented did not allow for the collection of data for consumers who are likely to purchase OTC omeprazole in other venues. To compare the study population to the U.S. population as a whole, the demographics of those consumers who purchased OTC omeprazole were compared to the 1999 U.S. census. Demographic indicators of the actual use population were similar to U.S. census reports, except that the study population had a slightly older mean age (expected, given the epidemiology of heartburn). In an additional attempt to detect selection bias, the actual use study population was compared to those with heartburn who did not enroll in the study. The lack of meaningful differences between these groups suggests that a strong systematic selection bias is unlikely. The study showed that accurate self-selection was made by a substantial majority of purchasers. When all 6 criteria were considered together, appropriate self-selection was 81%. Product users were highly compliant with

5 January 2004 SELF-SELECTION AND USE PATTERNS OF OTC OMEPRAZOLE 21 label dosing instructions. Overall, 79% of subjects were compliant with the 14-day regimen or contacted a physician during the trial. Only 34 subjects (5%) took more than 14 doses in the trial. Of these, 14 subjects (41%) contacted a physician during the trial, and 85% had contact with a physician about heartburn before, during, or soon after the trial. Only 5 subjects out of 758 (less than 1%) took more than 14 doses and did not contact a physician about their heartburn. Moreover, only 1 subject who took more than 14 doses and did not contact a physician self-reported that frequent heartburn had recurred. These data support the contention that OTC omeprazole can be used appropriately by consumers in the OTC setting. The product label encouraged consumers to consult with a healthcare professional regarding their heartburn. Overall, 75% of subjects in the trial had healthcare provider contact about heartburn before, during, or soon after the trial. Nearly as many subjects consulted a physician in association with this 3-month trial (34%) as had contacted a physician during the entire year before the trial (48%). Notably, 20% of subjects who had never previously contacted a physician about heartburn did so for the very first time during or soon after a trial of omeprazole. This study does not provide evidence for significant ongoing chronic use, either daily or as needed for symptoms. When recurrent symptoms after a 14-day regimen of omeprazole were assessed at the 3-month follow-up interview, 43% of subjects reported that frequent heartburn had not returned. Among those whose frequent heartburn returned, only 16 (4%) used more than 14 doses. Of those, all but 1 subject had physician contact regarding heartburn before, during, or soon after the trial. Therefore, among the 758 subjects who completed the study, only 1 subject took more than 14 doses, was not in any way under the care of a healthcare provider for heartburn, and had frequent heartburn return within 3 months. Proton pump inhibitors are not the first class of antisecretory drugs approved for use without a prescription. H 2 RAs were switched from prescription only to OTC status nearly a decade ago. This decision was supported by a decision analysis, which concluded that OTC H 2 RA would not lead to an unsafe delay in seeking treatment for gastric cancer. 3 OTC H 2 RA appeared to be not only a safe means of dyspepsia self-care but also less costly, because it was estimated that visits for dyspepsia would decrease by 1 million/year. 3 The OTC transition occurred in 1995 after completion of efficacy trials. 4,5 The impact of this transition was studied in Minnesota by Shaw et al. 6 more than 2 years after the first H 2 RA went OTC. An ambulatory population reported using the OTC H 2 RAs appropriately and as commonly as antacids. Expectations for the effectiveness of these medications were not met, however. As a sole treatment, complete relief was infrequently provided. The expected decline in physician visits for dyspeptic complaints did not occur. 6 This first actual use study of OTC omeprazole suggests that consumers carry out similar behaviors in terms of appropriate self-selection and physician contact for heartburn symptoms. In conclusion, actual use data support that consumers accurately differentiate between frequent and occasional heartburn, appropriately self-select whether the drug is appropriate for use, comply with a 14-day dosing regimen in the OTC setting, and appropriately seek physician involvement for longer-term management of frequent heartburn. References 1. Lind T, Havelund T, Lundell L, et al. On-demand therapy with omeprazole for the long-term management of patients with heartburn without esophagitis: a placebo controlled randomized trial. Aliment Pharacol Ther 1999;13: Bardhan KD, Muller-Lissner SA, Bigard MA, et al. Symptomatic gastro-oesophageal reflux disease: double-blind controlled study of intermittent treatment with omeprazole or ranitidine. BMJ 1999; 18: Oster G, Huse DM, Delea TE, et al. The risks and benefits of an Rx-to-OTC switch. Med Care 1990;28: Simon TJ, Berlin RG, Gardner AH, et al. Self-directed treatment of intermittent heartburn: a randomized, multicenter, double-blind, placebo-controlled evaluation of antacid and low doses of an H 2 receptor antagonist (famotidine). Am J Ther 1995;2: Gottlieb S, Decktor DL, Eckert JM, et al. Efficacy and tolerability of famotidine in preventing heartburn and related symptoms of upper gastrointestinal discomfort. Am J Ther 1995;2: Shaw MJ, Fendrick AM, Kane RL, et al. Self reported effectiveness and physician consultation rate in users of over-the-counter histamine-2 receptor antagonists. Am J Gastroenterol 2001;96: Address reprint requests to: A. Mark Fendrick, M.D., 300 North Ingalls Building, Room 7E06, Ann Arbor, Michigan amfen@umich.edu; fax: (734) Supported by Procter & Gamble Health Sciences Institute.