1 Omeprazole Magnesium Keith C. Triebwasser, Ph.D. Senior Director Regulatory Affairs Procter & Gamble

2 Rx to OTC Switch Omeprazole for the Prevention of Frequent Heartburn Symptoms

3 Target Population: People with Frequent Heartburn  Heartburn symptoms 2 or more days per week (40 million people)  Affects their daily lives  Goal: to prevent vs. treat symptoms

4 Target Population Tries to Manage Frequent Heartburn  77% use OTC medications  OTC product use - 80% use antacids - 48% use OTC H 2 RAs - 38% use both  Only 19% report satisfaction

5 Current OTC Therapies Not Well-Suited for People with Frequent Heartburn  Pharmacology limits effectiveness –Short duration of action –Intended for episodic heartburn  Current therapies lack all day efficacy

6 Omeprazole Ideally Suited for Target Population  Pharmacology provides for –Prolonged acid suppression –24 hour prevention of symptoms –Once daily dosing

7 Omeprazole Ideally Suited for Target Population  Omeprazole’s excellent safety profile –15 years –125 countries –450 million patient treatments

8 OTC Label Label clearly directs consumers:  How to select the product  How to use the product  What to do if symptoms continue or return

9 OTC Label Elements  Target population –Frequent heartburn sufferers (2 or more days/week)  Indication –Prevention of the symptoms of frequent heartburn for 24 hours

10 OTC Label Elements  Target population –Frequent heartburn sufferers (2 or more days/week)  Indication –Prevention of the symptoms of frequent heartburn for 24 hours  Dose –20 mg of omeprazole as omeprazole magnesium

11 OTC Label Elements  Target population –Frequent heartburn sufferers (2 or more days/week)  Indication –Prevention of the symptoms of frequent heartburn for 24 hours  Dose –20 mg of omeprazole as omeprazole magnesium  Directions for use –Take 1 tablet in the morning

12 OTC Label Elements  Target population –Frequent heartburn sufferers (2 or more days/week)  Indication –Prevention of the symptoms of frequent heartburn for 24 hours  Dose –20 mg of omeprazole as omeprazole magnesium  Directions for use –Take 1 tablet in the morning –Take every day for 14 consecutive days

13 OTC Label Elements  Target population –Frequent heartburn sufferers (2 or more days/week)  Indication –Prevention of the symptoms of frequent heartburn for 24 hours  Dose –20 mg of omeprazole as omeprazole magnesium  Directions for use –Take 1 tablet in the morning –Take every day for 14 days  Instructions to see a doctor –If you have warning signs –If heartburn continues or returns

14 Omeprazole, properly labeled, can be safely and effectively used in an OTC setting

15 Presentation Agenda OTC Omeprazole for Frequent Heartburn David Peura, M.D. Professor of Medicine Associate Chief of Gastroenterology, University of Virginia Efficacy and Consumer Use Douglas Bierer, Ph.D. Director, OTC Drug Development, The Procter & Gamble Co. Safe Use in OTC Setting Nora Zorich, M.D., Ph.D. Vice President, Pharmaceuticals, The Procter & Gamble Co. Summary Keith Triebwasser, Ph.D. Senior Director, Regulatory Affairs, The Procter & Gamble Co. Safety Douglas Levine, M.D. Chief Medical Officer, AstraZeneca LP

16 Proposed Omeprazole RX to OTC Switch: A Clinician’s Perspective David Peura, M.D. FACP FACG Professor of Medicine Associate Chief of Gastroenterology and Hepatology University of Virginia

17 Gap in OTC Therapy for Frequent Heartburn  Heartburn frequency varies  Current OTC meds are inadequate therapy for frequent HB  Condition does not require intensive physician involvement  Consumers could self-manage frequent HB with effective OTC therapy

18   More than 50% GI patients on PPIs   Primary care physicians comfortable prescribing PPIs for frequent heartburn   Endoscopy/diagnostic tests unnecessary for uncomplicated frequent heartburn   Symptom management/prevention is current practice Current Physician Experience With PPIs and Frequent Heartburn

19 OTC Omeprazole Consistent with Current Practice Guidelines Therapy should be aimed at treating or preventing heartburn symptoms with acid-reducing medications

20 Frequent Heartburn Can Be Self-Managed With OTC Omeprazole   Label encourages people to see their doctor   People will continue to see doctors   Low risk/high benefit to consumer

21 OTC Omeprazole Would Benefit Consumers   Symptom prevention is key   PPI best therapy to prevent frequent heartburn symptoms   Proposed dose and duration appropriate   Omeprazole safe and effective

22 Efficacy and Consumer Use Douglas Ws. Bierer, Ph.D. Director, OTC Drug Development Procter & Gamble

23 Efficacy and Consumer Behavior Program  Pivotal efficacy studies  Consumer understanding and behavior studies –Label comprehension –Appropriate OTC use

24 Efficacy Trials  Two efficacy trials  Study populations –Heartburn symptoms > 2 days a week –No physician diagnosis of GERD or erosive esophagitis  Dosing –One tablet in the morning for 14 consecutive days  Endpoint –% subjects heartburn-free –% days heartburn-free

25 Percent of Subjects Heartburn Free For 24 Hours: Time Course Over 14 Days Time (days) % Subjects With No Heartburn Study mg OME Study 171 Placebo Study mg OME Study 183 Placebo * p <.001 (day 1, day 14, across 14 days)

26 Conclusion: Efficacy Studies  20 mg provides prevention of heartburn symptoms for 24 hours  Uses: For the prevention of the symptoms of frequent heartburn for 24 hours  Dose: 20 mg  Directions: 1 tablet in the morning for 14 consecutive days

27 Consumer Understanding and Behavior Program  Objectives –Correct self-selection –Understand how to use product –Understand and adhere to product warnings  Studies –Label comprehension –Actual use

28 Label Comprehension Study Design  Subjects recruited from 12 sites across U.S. n=684  Study population –Infrequent or no heartburn –Frequent heartburn –Low-literacy with frequent heartburn –Potential drug-drug interactions –Pregnant/nursing

29 Label Comprehension Study Results Who Should Use the Product Infrequent/ No Heartburn 22% 78% Chose Correctly n=229

30 Label Comprehension Study Results Who Should Use the Product Frequent Heartburn 1% 99% Chose Correctly n=200

31 Label Comprehension of Low Literate People with Frequent Heartburn Frequent heartburn situations79% Infrequent heartburn situations49% % Correct Response (n=162)

32 Subjects Understood How to Use the Product 1 tablet per day95% Take for 14 consecutive days91% Contact healthcare professional before using beyond 14 days92%

33 Subjects Understood When Not to Use/Ask a Health Professional  Drug-drug interactions –Generic + brand names82% –Generic names alone50%  Pregnant/nursing91%  General warning signs81%

34 Actual Use Study: Objectives  Evaluate consumer use in naturalistic OTC setting –Correct self-selection –Appropriate use –Complied with label instructions

35 Actual Use Study Design  Design mimicked consumer purchase decisions: –Mall kiosk site – not clinical site –No health care professional on site –No subject contact in use phase –Purchase product –Product repurchase allowed

36 Follow-Up Interview 4 Weeks After Usage Period Product Use/ Repurchase 8 Week Period Study Phases Self Selection Decision At Mall Kiosk

37 Disposition of Subjects Population Approached at Mall n = 5060 Population Approached at Mall n = 5060 No Heartburn/ Not Interested Not Appropriate to use n = 3809 No Heartburn/ Not Interested Not Appropriate to use n = 3809 Said They Could Use Product n = 1251 Said They Could Use Product n = 1251 Would Not Purchase n = 385 Would Not Purchase n = 385 Agreed to Purchase Product [Self-Selection Population] n = 866 Agreed to Purchase Product [Self-Selection Population] n = 866

38 Demographics of Self-Selection Population Characteristic Gender (% female) 58% Race % Caucasian68% % African American16% % Hispanic11% Mean age/range 48/18-91 Low reading ability (REALM Test) 8% Heartburn symptoms  2days/wk 90% Use OTC heartburn medications 90% Use Rx heartburn medications40% n=866

39 Results of Self-Selection Correct self-selection of all 6 selection criteria: 81%  Heartburn  2 days per week   18 years of age  Not allergic to omeprazole  Not pregnant or nursing  No general warning signs  No drug-drug interactions n=866

40 People Who Did Not Correctly Self- Select  < 18 years of age3  Pregnant/nursing 1  Allergic to omeprazole 0  General warning signs 82  Drug-drug interactions 8  Infrequent heartburn 86 Number of Subjects n=866

41 Disposition of Subjects Who Purchased Product Agreed to Purchase Product [Self-Selection Population] n = 866 Agreed to Purchase Product [Self-Selection Population] n = 866 Withdrew Consentn = 4 Did Not Meet Study Criterian = 8 Withdrew Consentn = 4 Did Not Meet Study Criterian = 8 No Diary n = 96 No Diary n = 96 Used Product and Returned Diary [Use Population] n = 758 Used Product and Returned Diary [Use Population] n = 758

42 Subjects Are Compliant With Dosing Directions  No more than 1 tablet per dose96%99%  No more than 1 tablet per day91%98% Per Dosing Occasion Per Subject

43 Compliance With the 14-Day Dosing Regimen  Definition of compliance –80-100% of the product within 14 ± 3 days –Physician consultation if exceeded 14 doses (11-14 doses within days) (11-14 doses within days)

44 Compliance With the 14-Day Dosing Regimen People achieved high compliance with dosing directions 79% According to label directions 3% > 14 doses w/o doctor contact 9% doses in > 17 days < 1% Multiple daily doses 9% < 11 doses

45 Rx Therapy 15% Return of Frequent Heartburn Four Weeks After Trial No Medication 8% Antacids 22% H 2 RA 9% Antacids + H 2 RAs 3% No Frequent Heartburn 43%

46 Actual Use Study: Conclusions  Consumers appropriately self-select  Consumers understood the label  Consumers used product for prevention of frequent heartburn  Consumers used omeprazole according to label directions

47Summary  Indication –Prevention of the symptoms of frequent heartburn for 24 hours  Dose –20 mg of omeprazole as omeprazole magnesium  Directions for use –Take 1 tablet in the morning –Take every day for 14 days

48 Our proposed label, the efficacy data and the consumer’s ability to understand and use this product safely and appropriately are congruent

49 OTC Omeprazole Update on Safety Doug Levine, M.D. Chief Medical Officer AstraZeneca LP

50 OTC Omeprazole Product Safety Product safety is defined as adverse events occurring in relation to product use during short or long term Safety of omeprazole is established based on:  Clinical trials with Rx product  Rx post-marketing surveillance  OTC clinical trials Adverse event profile of omeprazole is established, and is acceptable for OTC

51 OTC Omeprazole Product Safety  Sponsor intent = short term use  If unintended long-term use occurs without medical supervision, product adverse event profile is acceptable (based on Rx product experience)

52 Long-term Safety Issues Not Directly Related to the Product  Potential consequences of consumer behavior without medically supervised use  Involves medical diseases other than acid reflux disease  Involves the natural history of acid reflux induced damage to the esophagus  Not directly linked to omeprazole

53 Long-term Safety Issues Not Directly Related to the Product  Not likely with alarm symptoms (labeled) –Dysphagia (trouble swallowing food) –Frequent chest pain –Unexplained weight loss –Frequent wheezing, chronic cough –Chest pain with shortness of breath; sweating; pain spreading to arm, neck or shoulders; or lightheadedness

54 Long-term Safety Issues Not Directly Related to the Product Possible with responders who do not seek medical advice (despite label instructions):  Non-neoplastic upper GI condition –Esophageal erosions –Gastric/duodenal ulcers  Upper GI malignancies  Upper GI conditions with risk of malignancy

55 Long-term Safety Issues Not Directly Related to the Product Unlikely with upper GI malignancy (esophagus, stomach)  Different symptoms (e.g., dysphagia, nausea, vomiting, early satiety, weight loss) do not respond to omeprazole  Malignancy usually present at first presentation for medical care, without antecedent heartburn, other symptoms  Malignancy is unusual in endoscoped populations with frequent heartburn

56 Long-term Safety Issues Not Directly Related to the Product Possible with upper GI conditions with risk of malignancy Barrett’s esophagus (complication of acid reflux induced esophageal damage)  Common, but rare progression to malignancy  Difficult to effectively manage cancer risk  Omeprazole does not increase cancer risk  Omeprazole does not induce regression

57 Heartburn and Esophageal Cancer  Increasing incidence of esophageal adenocarcinoma is not related to acid reducers  Afflicted patients generally present without heartburn or Barrett’s esophagus  Presently, incidence rate approximately equals mortality rate for this cancer, suggesting lack of clinical “signal” to draw medical attention  No evidence that acid reducers mask such “signals”  Cancer development is rare  Omeprazole does not increase cancer risk

58Conclusions  Product-related safety profile of omeprazole is acceptable  The natural history of esophageal acid reflux damage can involve rare, serious consequences  Omeprazole does not directly increase the risk of esophageal adenocarcinoma  Based on overall safety considerations, omeprazole is acceptable for OTC use

59 Benefit/Risk Assessment of Omeprazole in the OTC Market Nora Zorich, M.D., Ph.D. Vice President Pharmaceuticals Procter & Gamble

60 Considerations of Chronic Use of Omeprazole Without Physician Involvement 1.What proportion of consumers may use OTC omeprazole on a regular basis? 2.Do consumers with FHB go to their physicians? Will OTC omeprazole change that? 3.What benefits and risks might result from use without physician involvement?

61 NDC Prescription Database: PPI Use 1.What Proportion of Consumers May Use OTC Omeprazole on a Regular Basis? Patients (%) Rx Dispensed/Year

62 Bardhan Study Design 1.What Proportion of Consumers May Use OTC Omeprazole on a Regular Basis?  Patients with frequent heartburn  Controlled study to assess omeprazole usage pattern over 1 year period  Omeprazole 20mg daily for 14 days  If FHB returned (in 1 year) patients self managed additional courses of therapy Bardhan et al., BMJ, 1999, 18:

63 Bardhan Study Results 1.What Proportion of Consumers May Use OTC Omeprazole on a Regular Basis?  72% used intermittent 14-day regimens –Of these, 68% requested 3 or fewer treatment courses over the year –Symptom control after 2 weeks was a strong predictor of outcome  28% required maintenance therapy at some point during the year Bardhan et al., BMJ, 1999, 18:

64 Actual Use Trial Results No Frequent Heartburn 43% Antacids/ H 2 RAs/No Medicine 42% 1.What Proportion of Consumers May Use OTC Omeprazole on a Regular Basis? Rx Therapy 15%

65 1.What Proportion of Consumers May Use OTC Omeprazole on a Regular Basis?  Administrative claims database –21% used chronically  Published literature –28% required maintenance therapy  Actual Use Trial –15% returned to prescription PPI –An additional 4% took two or more 14 day regimens Most of the people who use omeprazole don’t use it chronically

66 1.What proportion of consumers may use OTC omeprazole on a regular basis?? 2.Do consumers with FHB go to their physicians? Will OTC omeprazole change that? 3.What benefits and risks might result from use without physician involvement? Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement

67 Oliveria Study Design 2.Do Consumers With FHB Go to Their Physicians?  Survey of 2000 people with heartburn  How they understand their heartburn  How they manage their symptoms  How often they have physician contact Oliveria et al., Arch Intern Med. 1999;159:

68 Oliveria Study Results 2.Do Consumers With FHB Go to Their Physicians?  Over 90% were taking therapy for symptoms  Physician contact directly correlates to the frequency of symptoms –People with frequent HB were 4 times more likely to see their physician –78% of people with most frequent HB had physician contact Oliveria et al., Arch Intern Med. 1999;159:

69 OTC H 2 RA’s Effect on Physician Visits 2.Do Consumers With FHB Go to Their Physicians? Will OME Change That?  Fallon Community Healthcare System –2000 patients with acid-related diseases  Minneapolis Cross-Sectional Survey ( ) –3400 consumers  MEDSTAT Marketscan data base ( ) –Database of >7 million people

70 Fallon Community Healthcare System Pre & Post OTC H 2 RA 2.Do Consumers With FHB Go to Their Physicians? Will OME Change That? GERD-related clinic visits/yr (mean) 7/95-7/967/94-7/95 3 SE Andrade et al, Med Care; 1999; 37:

71 Minneapolis Cross-Sectional Survey: Physician Visits in Past Year 2.Do Consumers With FHB Go to Their Physicians? Will OME Change That? Dyspepsia Heartburn 1997(n=1238)%1993(n=1141)% MJ. Shaw et al, Am J Gastroenterol 2001, 96(3):673-6

72 MEDSTAT Marketscan Data Base Do Consumers With FHB Go to Their Physicians? Will OME Change That? UGI Endoscopy (% of pop) Visits/UGI Dx Code (mean)

73 2.Do Consumers With FHB Go to Their Physicians? Will OME Change That?  Rate of physician consultation for heartburn doubled during the study  20% contacted a doctor for the first time about their heartburn during the study  53% of people taking more than 14 doses, talked to their physician during or just after the study Actual Use Trial Results

74 2.Do Consumers With FHB Go to Their Physicians? Will OME Change That?  The majority of people with FHB see a doctor for their symptoms  Physician visits stayed the same after H 2 RA’s were available OTC  The Actual Use Trial suggests that physician visits will not decrease and may increase with OTC omeprazole

75 1.What proportion of consumers may use OTC omeprazole on a regular basis? 2.Do consumers with FHB go to their physicians? Will OTC omeprazole change that? 3.What benefits and risks might result from use without physician involvement? Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement

76 3.Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement  The label is clear - see physician if FHB returns  OTC omeprazole a better option than current OTC therapies Benefit to User

77 Short-term PPI Superior to Long-Term H 2 RA for Healing of Esophagitis Chiba et al., Gastroenterology 1997, 112:

78 3.Considerations of OTC Chronic Use of Omeprazole Without Physician Involvement  The majority of consumers won’t use chronically  Consumers who use chronically will involve their physician  The risks of use without physician involvement are minimal and the benefits are substantial

79Summary  Omeprazole will fill a critical gap in OTC for frequent heartburn  The target population is those people with frequent heartburn  The label is understood and it is congruent with OTC omeprazole use  The label should specify a 14-day regimen  Omeprazole is acceptable for use OTC

80Conclusion Omeprazole can be safely and effectively used OTC

81