1. 1 Clinical Overview Omeprazole Magnesium (Prilosec 1 TM ) June 21, 2002 Mark Avigan, MD CM Division of Gastrointestinal and Coagulation Drug Products CDER, FDA

2. 2 Initial Proposed Indications for OTC Omeprazole Mg The relief of heartburn, acid indigestion and sour stomach The prevention of heartburn, acid indigestion and sour stomach brought on by consuming food and beverages or other inciting events The prevention of symptoms for 24 hours (Joint Advisory Committee Oct 20, 2000)

3. 3 Conclusions of First Advisory Committee Treatment of episodic heartburn as a symptom –Studies 092 and 095 were negative 4 hour prevention of meal-induced heartburn –Studies 005 and 006 did not consistently demonstrate efficacy The prevention of symptoms for 24 hours –Studies 171 and 183 both demonstrated efficacy

4. 4 Pharmacological Characteristics of Omeprazole-Mg Half-life: 1-2 hours Irreversibly binds gastric H+K+ ATPase Dosing interval: 24 hours Minimal acid suppression after single dose Buildup of PD response over a few days

5. 5 The increase of acid suppression over consecutive daily doses may reinforce continuous unsupervised usage by consumers seeking optimal relief of chronic heartburn

6. 6 Overview of Presentation Safety Profile of Omeprazole Potential for Long-term OTC Usage Results of Pivotal Studies 171 and 183 Symptoms and Usage in Actual Use Study 007 Issues to Resolve

7. 7 Omeprazole-Mg Safety Profile Toxicity of Short-Term Exposure hypersensitivity reactions toxic epidermal necrolysis agranulocytosis liver injury

8. 8 Drug-Drug Interactions Inhibition of CYP 2C19 –warfarin, phenytoin, diazepam, digoxin Gastric acid neutralization –ketoconazole

9. 9 Safety Issues of Long-term OTC Exposure Masking and/or delay in dx of GERD complications and malignancy Tumorigenic potential of drug-induced hypergastrinemia and drug-related genotoxicity

10. 10 Potential for Long-term OTC Usage Effective in heartburn prevention but not treatment of episodes Heartburn recurrence rate is high Actual Use studies demonstrate continued unsupervised treatment exceeding labeled instructions

11. 11 Currently Proposed Indications Prevention of symptoms of frequent heartburn for 24 hrs Only for those who suffer heartburn two or more days a week

12. 12 Efficacy Studies Studies 171 and 183 - double blind placebo controlled 2 week treatment studies; n=500 subjects/treatment arm Inclusion criteria - presence of heartburn on at least 2 days/week Primary efficacy variable - No heartburn over 24 hours between the 1 st and 2 nd daily dose

13. 13 Study Results Subjects with no heartburn: Day 1 Day 14 –Placebo 32% 43% –Ome-Mg (20 mg) 48% 72% Therapeutic gain of Ome-Mg 20 mg vs placebo only 16% on Day 1 Therapeutic gain increased to 29% on Day 14 After 14 days of treatment almost 30% of subjects experienced breakthrough heartburn

14. 14 Influence of Baseline Heartburn Frequency on Responses Heartburn frequency Therapeutic Gain (Drug - Placebo) % Patients with No Heartburn % of Days Day 1 Day 14 <50% 4 % 11% 100% 18% 39%

15. 15 Conclusions Subjects with Low Frequency Heartburn Therapeutic gain was small because of high placebo response rate Subjects with Daily Heartburn Therapeutic gain was higher because of low placebo response rate Breakthrough heartburn was 40% after 14 days of treatment

16. 16 GERD* Chronic symptoms (e.g. heartburn) or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus Many patients with GERD require long-term, possibly life-long, therapy *Updated Guidelines for the Diagnosis and Treatment of GERD; Am. J. Gastro., 1999

17. 17 Characterization of Study Patients High degree of overlap with dx of GERD After treatment in both studies the recurrence of heartburn was rapid Within 3 days after treatment stopped –the therapeutic gain disappeared –the daily percentage of subjects with heartburn over 24 hours rose to 55%

18. 18 Actual Use Study >90% experienced heartburn for >1 yr and 50% for > 5 yrs 57% experienced heartburn 4 or more days/wk Many subjects used other products or prescription medications to relieve recurrent heartburn Studies have not measured the potential for long- term intermittent usage

19. 19 Cautions Listed in Proposed Labeling ‘notify your doctor if you have had heartburn for 3 months or longer without talking to your doctor’ ‘stop use and ask a doctor if heartburn continues or returns after using this product everyday for 14 days’ ‘do not continue beyond 14 days unless directed by a doctor’

20. 20 Issues to Resolve Does a single 14 day treatment course meet the short and long-term needs of consumers? Is unsupervised chronic intermittent usage consistent with the sponsor's proposal? Is restriction to a single 14 day treatment course an important safety feature?