OTC Omeprazole Magnesium (Prilosec 1 TM )

1. OTC Omeprazole Magnesium (Prilosec 1TM) October 20, 2000 Larry Goldkind MD Division of Gastrointestinal and Coagulation Drug Products CDER, FDA

2. Efficacy • Pharmacodynamics • Review of Efficacy Trials • Current Prescription Usage of Prilosec for GERD/Heartburn • Definitions of GERD: Heartburn • Current OTC template for Heartburn Medications • ProposedPrilosec 1 OTC label • Summary

3. Pharmacokinetics and Pharmacodynamics • Short pharmacokinetic half-life: 0.5-1 hour • Slow pharmacodynamic onset: Acid inhibition only 50% of maximum at 24 hours • Long acting pharmacodynamic effect: acid secretion returns to baseline over 3-5 days

4. Single-Dose Pharmacodynamic Study: Astra Merck Protocol 129Intragastric pH vs.. time post-dose ??

5. Repeat Dose PharmacodynamicsReference #44(mean pentagastrin stimulated peak acid output- mmol H/hour

6. Heartburn Relief Trials: Studies 092 and 095

7. Demographics of Studies 092/095 • Mean frequency of heartburn: 60% of days • Average heartburn severity: 1.8-1.9 (Scale 0-3: moderate=2) • Over 50 % of subjects had heartburn severity > 2

8. Primary Efficacy Endpoint:Sustained Complete Relief First Episode/First Dose

9. Secondary EndpointsFirst dose Inconsistent results • Sustained adequate relief • Complete relief within 1 hour • Adequate relief within 1 hour • Overall assessment

10. Secondary Analysis“All Episodes Analysis” • Extent of exposure: almost 90% took more than 3 doses • Results beyond first episode are confounded by pharmacodynamic carry-over effect from prior doses • No benefit shown for current OTC occasional episodic usage

11. Sustained Complete Relief “All Episodes” Separated by at Least 4 days

12. Additional Heartburn Relief Studies • 3 studies : 017, 018 and 019 • 11,700 subjects enrolled • No efficacy at study endpoints: Sustained complete relief Sustained adequate relief Overall assessment of study medication Backup medication

13. Summary of Episodic Heartburn Relief • 5 studies of episodicheartburn relief: Primary analyses all failed • “All episodes analysis” failed to demonstrate efficacy for occasional episodic usage

14. Prevention of Meal-Induced Heartburn 2 studies : 005 ; 006

15. Primary Efficacy EndpointHeartburn-Free:4 Hours Post Meal(% subjects heartburn-free)

16. Secondary Endpoints Supportive Results: 20 mg dose • Overall assessment of medication • Maximum severity score • Backup medication use • Average symptom severity • Reduction of maximum severity score

17. Secondary Endpoints Supportive Results: 10 mg dose Maximum Severity Score Not Supportive • Overall assessment • Backup medication use • Average symptom severity • Reduction of maximum severity score

18. Conclusions • Prilosec 1 at 20 mg dose mayhave marginal efficacy for the prevention of heartburn when taken 1 hour before a heartburn inducing meal • Prilosec 1 at 10 mg dose lacks replicated efficacy for primary and most meaningful secondary endpoints

19. Conclusions (cont.) Outstanding issues • Unreplicated results • Small therapeutic gains compared to placebo • Consumer confusion due to lack of benefit heartburn relief • Pharmacodynamics favor chronic use

20. 24-Hour PreventionStudies 171 and 183 New indication: 24 hour prevention of symptoms for up to 10 days Is this management of GERD?

21. Entry Criteria • Heartburn of greater than 1 month duration • Heartburn at least 2 days per week • Antacid or OTC H2-RA responsive heartburn in the past (enriched population)

22. Demographics • 80% of subjects: baseline frequency > 50% of days • Mean severity 1.5 (2=moderate severity)

23. Primary Efficacy EndpointHeartburn-Free Day 1(% subjects)

24. Day 14 Heartburn-Free(% subjects)

25. Summary of Results • Replicated statistically significant difference compared to placebo • Efficacy both doses • Efficacy increases over time Day 1: Therapeutic gain 9-17% Day 14: Therapeutic gain 23-30%

26. Time to Recurrence of Heartburn(% of Subjects Heartburn-Free Post-Treatment)

27. Conclusions: Daily Dose 24-Hour Prevention Studies • Successful prevention of heartburn symptoms with 10mg & 20mg doses • Increased efficacy over time • Benefit lost within 3 days of discontinuation

28. Prescription vs. OTC GERD vs. Heartburn

29. Current Prescription Prilosec Label for GERD Gastroesophageal Reflux Disease (GERD) • “The recommended adult oral dose of Prilosec for treatment of patients with symptomatic GERD and no esophageal lesions is 20 mg daily for up to 4 weeks • The recommended oral dose for the treatment of patients with erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily for 4-8 weeks"

30. What Is GERD? Sponsor definition: (page 40 of summary volume) “GERD represents a distinct physician-diagnosed chronic disease characterized by acid reflux and attendant symptoms, usually heartburn …... and requires 4-8 weeks treatment with omeprazole” “Episodic treatment of heartburn is different from the treatment of GERD.” • Differences not specified

31. Definitions of GERD “GERD may be defined as symptoms and/or tissue injury related to the reflux of gastric contents into the esophagus…….Heartburn is the typical symptom of GERD”(American Society of Gastrointestinal Endoscopy-Guidelines for the Practice of Endoscopy) “ GERD is used to describe any symptomatic clinical or histopathologic alteration resultant from episodes of gastroesophageal reflux” (Gastrointestinal diseases; Sleisenger and Fortran)

32. Definition of GERD (cont.) Entry criteria from published studies: “Patients with a history of heartburn for over 12 months and episodes of moderate to severe heartburn on 4 or more of the seven days before endoscopy” (“Efficacy of omeprazole for the treatment of symptomatic acid reflux disease without esophagitis” Arch Intern Med., June 26, 2000)

33. Summary:Heartburn vs. GERD Heartburn is the cardinal symptom of GERD GERD • Assessment of GERD requires medical judgement • Management of GERD is based on medical judgement • Severity • Chronicity • Frequency

34. Rationale for OTC Treatment of Episodic Heartburn • Discrete, episodic, occasional symptoms • Symptoms responsive to low-dose therapy (1/8 to 1/4 daily prescription dose of acid suppressive therapies) • OTC product is effective at relief and prevention • No repeat dose carry-over effects required • 2-week limited usage

35. Current Template for OTC Acid Suppressive Agents for Heartburn • For relief of episodic symptoms: • To prevent symptoms: before eating food or drinking beverages that cause heartburn • Note: indication linked to a specific episode of heartburn

36. Proposed Prilosec 1 OTC label • For relief of symptoms: No efficacy • For 24 hour prevention: take anytime during the day: No data presented

37. Proposed Prilosec 1 OTC label(cont.) • or if you prefer, one hour before those events associated with occasional heartburn……. such as consuming food, beverages: Marginal efficacy supported stress, hectic lifestyle, lying down, or exercise: No supportive data presented

38. Proposed Prilosec 1 OTC Label (cont.) • 24 hour prevention is a new indication for OTC heartburn treatment and is not episodic • Dose any time of day is an unsupported new dosing instruction and is not episodic • Non-meal related symptom prevention is an unsupported new indication • Proposed dose is prescription dose for GERD

39. Overall Conclusions Pharmacodynamic properties predict: • No efficacy for relief (acute treatment) • Progressive improvement in efficacy for preventionover time (delayed PD effect)

40. Overall Conclusions (Cont) Results of clinical studies follow PD predictions: • No efficacy at acute treatment of episodic heartburn • Marginal efficacy at 1 hour prevention • Optimal role in prevention of heartburn over time in the management of GERD, currently “a physician- diagnosed chronic disease requiring 4-8 weeks of therapy”