Procter & Gamble Company

AstraZeneca LP

Omeprazole Magnesium Tablets

NDA No. 21-229

Advisory Committee

Briefing Document

May 6, 2002

Procter & Gamble Company / AstraZeneca LP

Omeprazole Magnesium Tablets

NDA No. 21-229

Advisory Committee

Briefing Document

May 6, 2002

Available for Public Disclosure Without Redaction

# [List of Tables 4](#__RefHeading___Toc9124576) {#list-of-tables-4 .TOC-1}

# [List of Figures 6](#__RefHeading___Toc9124577) {#list-of-figures-6 .TOC-1}

# [List of Study Numbers and Abbreviations 9](#__RefHeading___Toc9124578) {#list-of-study-numbers-and-abbreviations-9 .TOC-1}

# [Briefing Document Organization 10](#__RefHeading___Toc9124579) {#briefing-document-organization-10 .TOC-1}

# [1. Overview of the Briefing Document 11](#overview-of-the-briefing-document) {#overview-of-the-briefing-document-11 .TOC-2}

# [1.1 Introduction 11](#introduction) {#introduction-11 .TOC-3}

# [1.2 Executive Summary 14](#executive-summary) {#executive-summary-14 .TOC-3}

[1.2.1 Target Population: The Consumer Population with Frequent
Heartburn
14](#target-population-the-consumer-population-with-frequent-heartburn)

[1.2.2 Pharmacology of Omeprazole 14](#pharmacology-of-omeprazole)

[1.2.3 Safety 14](#safety)

[1.2.4 Efficacy 16](#efficacy)

[1.2.5 Proposed Dose and Duration for OTC Status
16](#proposed-dose-and-duration-for-otc-status)

[1.2.6 Consumer Label Understanding and Actual Product Use
18](#consumer-label-understanding-and-actual-product-use)

[1.2.7 Risk and Benefit of Ome-Mg in the OTC Setting
19](#risk-and-benefit-of-ome-mg-in-the-otc-setting)

[1.2.8 The Proposed OTC Label for Ome-Mg
20](#the-proposed-otc-label-for-ome-mg)

# [2. Characterization of the Consumer With Frequent Heartburn 22](#characterization-of-the-consumer-with-frequent-heartburn) {#characterization-of-the-consumer-with-frequent-heartburn-22 .TOC-2}

# [2.1 The Frequent Heartburn Population 22](#the-frequent-heartburn-population) {#the-frequent-heartburn-population-22 .TOC-3}

# [2.2 Medication Habits and Practices of the Frequent Heartburn Population 24](#medication-habits-and-practices-of-the-frequent-heartburn-population) {#medication-habits-and-practices-of-the-frequent-heartburn-population-24 .TOC-3}

# [2.3 Medical Utilization Patterns of the Frequent Heartburn Population 25](#medical-utilization-patterns-of-the-frequent-heartburn-population) {#medical-utilization-patterns-of-the-frequent-heartburn-population-25 .TOC-3}

# [2.4 Continuing Health Care Utilization Patterns 25](#continuing-health-care-utilization-patterns) {#continuing-health-care-utilization-patterns-25 .TOC-3}

# [2.5 Professional Recommending Patterns 26](#professional-recommending-patterns) {#professional-recommending-patterns-26 .TOC-3}

# [2.6 Heartburn Treatment Guidelines 26](#heartburn-treatment-guidelines) {#heartburn-treatment-guidelines-26 .TOC-3}

# [2.7 Overall Summary 26](#overall-summary) {#overall-summary-26 .TOC-3}

# [3. Clinical Pharmacology of Omeprazole 28](#clinical-pharmacology-of-omeprazole) {#clinical-pharmacology-of-omeprazole-28 .TOC-2}

# [3.1 Inhibition of Gastric Acid Secretion 29](#inhibition-of-gastric-acid-secretion) {#inhibition-of-gastric-acid-secretion-29 .TOC-3}

# [4. Summary of Safety 34](#summary-of-safety) {#summary-of-safety-34 .TOC-2}

# [4.1 Brief Summary of Safety Information Submitted in the Original NDA 21-229 34](#brief-summary-of-safety-information-submitted-in-the-original-nda-21-229) {#brief-summary-of-safety-information-submitted-in-the-original-nda-21-229-34 .TOC-3}

[4.1.1 Clinical Trials from the OTC Development Program with Omeprazole
Magnesium Multiple Unit Pellet System (MUPS) Tablets
34](#clinical-trials-from-the-otc-development-program-with-omeprazole-magnesium-multiple-unit-pellet-system-mups-tablets)

[4.1.2 Clinical Trials from Prescription Omeprazole Capsules
35](#clinical-trials-from-prescription-omeprazole-capsules)

[4.1.3 Prescription Omeprazole Post‑Marketing Surveillance Data
36](#prescription-omeprazole-postmarketing-surveillance-data)

# [4.2 Safety Update Report 36](#safety-update-report) {#safety-update-report-36 .TOC-3}

[4.2.1 Clinical Trial Data 36](#clinical-trial-data)

[4.2.2 Post-Marketing Data-- Ome-Mg (MUPS) Tablet Formulation - SUR
37](#post-marketing-data-ome-mg-mups-tablet-formulation---sur)

# [4.3 Updated Safety Information Included in the Resubmission of NDA 21-229 37](#updated-safety-information-included-in-the-resubmission-of-nda-21-229) {#updated-safety-information-included-in-the-resubmission-of-nda-21-229-37 .TOC-3}

[4.3.1 Clinical Trial Adverse Event Data from P&G Actual Use Study
2001007
38](#clinical-trial-adverse-event-data-from-pg-actual-use-study-2001007)

[4.3.2 Updated Post-Marketing Data -- Omeprazole magnesium (MUPS) Tablet
Formulation
38](#updated-post-marketing-data-omeprazole-magnesium-mups-tablet-formulation)

# [4.4 Other Safety Related Issues 39](#other-safety-related-issues) {#other-safety-related-issues-39 .TOC-3}

[4.4.1 Drug/Drug Interactions 39](#drugdrug-interactions)

[4.4.2 Unintended Use in Special Populations
39](#unintended-use-in-special-populations)

[4.4.2.1 Pregnancy 39](#pregnancy)

[4.4.2.2 Pediatric/Adolescents 40](#pediatricadolescents)

# [4.5 Overall Safety Conclusion 41](#overall-safety-conclusion) {#overall-safety-conclusion-41 .TOC-3}

# [5. Clinical Program Overview 42](#clinical-program-overview) {#clinical-program-overview-42 .TOC-2}

# [6. Efficacy Program 43](#efficacy-program) {#efficacy-program-43 .TOC-2}

# [6.1 Study Design and Clinical Methods 43](#study-design-and-clinical-methods) {#study-design-and-clinical-methods-43 .TOC-3}

[6.1.1 Statistical Methods 44](#statistical-methods)

[6.1.2 Demographics and Other Baseline Characteristics
44](#demographics-and-other-baseline-characteristics)

# [6.2 Efficacy Results 45](#efficacy-results) {#efficacy-results-45 .TOC-3}

[6.2.1 Primary Efficacy Parameter (Heartburn-Free for 24 Hours)
45](#primary-efficacy-parameter-heartburn-free-for-24-hours)

[6.2.2 Secondary Parameters 52](#secondary-parameters)

[6.2.3 Results with Ome-Mg 10: Primary Efficacy Parameter
(Heartburn-Free for 24 Hours): Day 1 and Across All 14 Days, and
Dose-Response
55](#results-with-ome-mg-10-primary-efficacy-parameter-heartburn-free-for-24-hours-day-1-and-across-all-14-days-and-dose-response)

[6.2.4 Outcomes During the Follow-up Phase
59](#outcomes-during-the-follow-up-phase)

# [6.3 Efficacy Conclusions 59](#efficacy-conclusions) {#efficacy-conclusions-59 .TOC-3}

# [7. Consumer Understanding and Behavior Program 60](#consumer-understanding-and-behavior-program) {#consumer-understanding-and-behavior-program-60 .TOC-2}

# [7.1 Label Comprehension Study Number 02255 60](#label-comprehension-study-number-02255) {#label-comprehension-study-number-02255-60 .TOC-3}

[7.1.1 Methods 60](#methods)

[7.1.2 Results 63](#results)

[7.1.3 Summary 63](#summary)

# [7.2 Label Comprehension Study Number 12179 64](#label-comprehension-study-number-12179) {#label-comprehension-study-number-12179-64 .TOC-3}

[7.2.1 Methods 65](#methods-1)

[7.2.2 Results 66](#results-1)

[7.2.3 Summary 66](#summary-1)

# [7.3 De-Selection Study Number US0117859 in Consumers With Infrequent Heartburn 67](#de-selection-study-number-us0117859-in-consumers-with-infrequent-heartburn) {#de-selection-study-number-us0117859-in-consumers-with-infrequent-heartburn-67 .TOC-3}

[7.3.1 Methods 67](#methods-2)

[7.3.2 Results 67](#results-2)

[7.3.3 Summary 67](#summary-2)

# [7.4 Usage Study Number 2001007 68](#usage-study-number-2001007) {#usage-study-number-2001007-68 .TOC-3}

[7.4.1 Methods 68](#methods-3)

[7.4.2 Results 70](#results-3)

[7.4.2.1 Demographics of the Self-Selection Population
70](#demographics-of-the-self-selection-population)

# [8. Overall Summary of Consumer Behavior (Label Comprehension and Actual Use Studies) 78](#__RefHeading___Toc9124646) {#overall-summary-of-consumer-behavior-label-comprehension-and-actual-use-studies-78 .TOC-2}

# [8.1 Ability of the Consumer to Correctly Self-Select the Product for Use 78](#ability-of-the-consumer-to-correctly-self-select-the-product-for-use) {#ability-of-the-consumer-to-correctly-self-select-the-product-for-use-78 .TOC-3}

# [8.2 Ability of the Consumer Population to Use the Product as Directed 78](#ability-of-the-consumer-population-to-use-the-product-as-directed) {#ability-of-the-consumer-population-to-use-the-product-as-directed-78 .TOC-3}

# [8.3 Ability of the Consumer to Understand the Warnings on the Label 79](#ability-of-the-consumer-to-understand-the-warnings-on-the-label) {#ability-of-the-consumer-to-understand-the-warnings-on-the-label-79 .TOC-3}

# [8.4 Ability of Consumers to Understand When to Consult a Physician 80](#ability-of-consumers-to-understand-when-to-consult-a-physician) {#ability-of-consumers-to-understand-when-to-consult-a-physician-80 .TOC-3}

# [8.5 Conclusion 81](#conclusion) {#conclusion-81 .TOC-3}

# [9. Risk/Benefit of Omeprazole Magnesium in the OTC Setting 82](#riskbenefit-of-omeprazole-magnesium-in-the-otc-setting) {#riskbenefit-of-omeprazole-magnesium-in-the-otc-setting-82 .TOC-2}

# [10. References 86](#references) {#references-86 .TOC-2}

[]{#__RefHeading___Toc9124576 .anchor}List of Tables

**[Page]{.underline}**

[Table 3.1 Ratios of Geometric Means and 95% Confidence Intervals for
AUC~0~ Subjects with Complete Pharmacokinetic Data
29](#table-3.1-ratios-of-geometric-means-and-95-confidence-intervals-for-auc0-subjects-with-complete-pharmacokinetic-data)

[Table 6.1 Demographic and Other Baseline Characteristics (Studies 171
and 183)
45](#table-6.1-demographic-and-other-baseline-characteristics-studies-171-and-183)

[Table 6.3 Analysis of Primary Efficacy Variable No Heartburn over 24
Hours on Day 1 Intent-to-Treat Subjects
47](#table-6.3-analysis-of-primary-efficacy-variable-no-heartburn-over-24-hours-on-day-1-intent-to-treat-subjects)

[Table 6.4 Number and Percent of Subjects with no heartburn over 24
hours, by day Study 171: Intent-to-Treat Subjects
49](#table-6.4-number-and-percent-of-subjects-with-no-heartburn-over-24-hours-by-day-study-171-intent-to-treat-subjects)

[Table 6.5 Number and Percent of Subjects with no heartburn over 24
hours, by day Study 183: Intent-to-Treat Subjects
50](#table-6.5-number-and-percent-of-subjects-with-no-heartburn-over-24-hours-by-day-study-183-intent-to-treat-subjects)

[Table 6.6 Analysis of Secondary Efficacy Variables Percentage of
Subjects with No Nocturnal and No More than Mild Heartburn on Day 1
Multiple-Dose Prevention Studies: Heartburn Over a Full Day
Intent-to-Treat Subjects
52](#table-6.6-analysis-of-secondary-efficacy-variables-percentage-of-subjects-with-no-nocturnal-and-no-more-than-mild-heartburn-on-day-1-heartburn-over-a-full-day-intent-to-treat-subjects)

[Table 6.7 Mean Percentage of Days (Adjusted) with Indicated Outcome
Over 14 Days of Double-Blind Phase^a^ Heartburn Over a Full Day
Intent-to-Treat Subjects
53](#table-6.7-mean-percentage-of-days-adjusted-with-indicated-outcome-over-14-days-of-double-blind-phasea-heartburn-over-a-full-day-intent-to-treat-subjects)

[Table 6.8 Analysis of Efficacy Variables Using GEE Treatment
Comparisons Based on All 14 days of Double-Blind Phase Heartburn Over a
Full Day Intent-to-Treat Subjects
54](#table-6.8-analysis-of-efficacy-variables-using-gee-treatment-comparisons-based-on-all-14-days-of-double-blind-phase-heartburn-over-a-full-day-intent-to-treat-subjects)

[Table 6.9 Mean Percentage of Days (Adjusted) with Indicated Outcome
Over 14 Days of Double-Blind Phase^a^ Heartburn Over a Full Day
Intent-to-Treat Subjects
55](#table-6.9-mean-percentage-of-days-adjusted-with-indicated-outcome-over-14-days-of-double-blind-phasea-heartburn-over-a-full-day-intent-to-treat-subjects)

[Table 6.10 Analysis of Efficacy Variables Using GEE Treatment
Comparisons Based on All 14 days of Double-Blind Phase Heartburn Over a
Full Day Intent-to-Treat Subjects
56](#table-6.10-analysis-of-efficacy-variables-using-gee-treatment-comparisons-based-on-all-14-days-of-double-blind-phase-heartburn-over-a-full-day-intent-to-treat-subjects)

[Table 6.11 Number and Percent of Subjects with no heartburn over 24
hours, by day Study 171: Intent-to-Treat Subjects
57](#table-6.11-number-and-percent-of-subjects-with-no-heartburn-over-24-hours-by-day-study-171-intent-to-treat-subjects)

[Table 6.12 Number and Percent of Subjects with no heartburn over 24
hours, by day Study 183: Intent-to-Treat Subjects
58](#table-6.12-number-and-percent-of-subjects-with-no-heartburn-over-24-hours-by-day-study-183-intent-to-treat-subjects)

[Table 6.13 Number of Days to First Occurrence of Heartburn During
Follow-up Phase (After Two Weeks Daily Dosing) Per-Protocol Subjects
59](#table-6.13-number-of-days-to-first-occurrence-of-heartburn-during-follow-up-phase-after-two-weeks-daily-dosing-per-protocol-subjects)

[Table 7.1 Label Comprehension Study Cohort Information Study 02255
62](#table-7.1-label-comprehension-study-cohort-information-study-02255)

[Table 7.2 Demographic Comparison Of Subjects who Purchased Product and
Returned Diary or Did not Return Diary Actual Use Study 007
71](#table-7.2-demographic-comparison-of-subjects-who-purchased-product-and-returned-diary-or-did-not-return-diary-actual-use-study-007)

List of Tables (Continued)

**[Page]{.underline}**

[Table 7.3 Comparison of Relapse Endpoints in Studies with GERD Patients
in the Rx Setting Vs. Studies with Frequent Heartburn Subjects in the
OTC Efficacy and Use Studies
75](#table-7.3-comparison-of-relapse-endpoints-in-studies-with-gerd-patients-in-the-rx-setting-vs.-studies-with-frequent-heartburn-subjects-in-the-otc-efficacy-and-use-studies)

[]{#__RefHeading___Toc9124577 .anchor}List of Figures

**[Page]{.underline}**

[Figure 2.1 Frequency of Heartburn in the United States Heartburn
Population (1997)^3^ 23](#__RefHeading___Toc9124670)

[Figure 2.2 Volume of OTC Heartburn Product Use by Frequency of
Heartburn (All OTC Users Past 12 months) 24](#__RefHeading___Toc9124671)

[Figure 3.1 Effect of Single Oral Doses of Omeprazole Suspension on
Pentagastrin Stimulated Gastric Acid Secretion in Healthy Subjects (n=6)
29](#__RefHeading___Toc9124672)

[Figure 3.2 Duration of Action of Two Different Single Oral Doses of
Omeprazole Suspension Estimated by Repeated Measurements of Pentagastrin
Stimulated Gastric Acid Secretion in Healthy Subjects (n=6)
30](#_Ref478176761)

[Figure 3.3 Individual Values for Percentage Reduction of Pentagastrin
Stimulated Gastric Acid Secretion Measured Both 6 and 24 Hours After the
5^th^ Dose of Omeprazole in Healthy Subjects (n=8) 31](#_Ref478176857)

[Figure 3.4 The Inhibitory Effects of 1 Week of Treatment with Different
Daily Doses of Ome on the 24-Hour Intragastric Acidity^71^
32](#__RefHeading___Toc9124676)

[Figure 3.5 Dose Response Curve for Repeated Once Daily Doses of
Omeprazole 33](#__RefHeading___Toc9124678)

[Figure 6.1 Study Schematic for 14-Day Heartburn Prevention Trials
43](#__RefHeading___Toc9124680)

[Figure 6.2 Percent of Subjects with 24 Hour Prevention of Heartburn ---
Day 1 46](#__RefHeading___Toc9124681)

[Figure 6.3 Percent of Subjects with 24 Hour Prevention of Heartburn ---
Time Course Over 14 Days Studies 171 and 183
48](#__RefHeading___Toc9124682)

[Figure 6.4 Percent of Days with No Heartburn --- Across 14 Day Dosing
Period 51](#__RefHeading___Toc9124684)

List of Abbreviations and Definition of Terms

  ------------------ -- -------------------------------------------------
  **Abbreviation**      **Definition**

  ACG                   American College of Gastroenterology

  AE                    Adverse Event

  ANOVA                 Analysis of Variance

  AUC                   Area Under the Curve

  AZLP                  AstraZeneca Limited Partnership

  CI                    Confidence Interval

  EE                    Erosive Esophagitis

  FDA                   Food and Drug Administration

  GDAC                  Gastroesophageal Reflux Disease

  GEE                   Generalized Estimating Equation

  GERD                  Gastroesophageal Reflux Disease

  H~2~RA(s)             Histamine H~2~-receptor Antagonist(s)

  ITT                   Intent-to-Treat

  mg                    Milligram

  MUPS                  Multiple Unit Pellet System

  NDA                   New Drug Application

  NDAC                  New Drug Advisory Committee

  Ome                   Omeprazole

  Ome-Mg                Omeprazole Magnesium

  Ome-Mg 10             Omeprazole Magnesium 10.3 mg

  Ome-Mg 20             Omeprazole Magnesium 20.6 mg

  OTC                   Over-the-Counter

  P&G                   The Procter & Gamble Company

  PPI                   Proton Pump Inhibitors

  REALM                 Rapid Estimate of Adult Literacy in Medicine

  R~x~                  Prescription
  ------------------ -- -------------------------------------------------

List of Abbreviations and Definition of Terms (Continued)

  ------------------ -- -------------------------------------------------
  **Abbreviation**      **Definition**

  SAE                   Serious Adverse Event

  SD                    Standard Deviation

  SUR                   Safety Update Report

  TEN                   Toxic Epidermal Necrolysis

  t~½~                  Elimination Half-Life

  U.S. or US            United States

  vs.                   Versus
  ------------------ -- -------------------------------------------------

[]{#__RefHeading___Toc9124578 .anchor}List of Study Numbers and
Abbreviations

  ------------------- -- -------------------------------------------------
  **Abbreviation**       **Study Number**

  007                    2001007

  171                    AMI 171

  183                    AMI 183

  02255                  02255

  12179                  12179
  ------------------- -- -------------------------------------------------

[]{#__RefHeading___Toc9124579 .anchor}Briefing Document Organization

1.  Part 1 of this document presents an overview of the briefing
    document.

2.  Part 2 characterizes the heartburn consumer.

3.  Part 3 presents summaries of the clinical pharmacology of
    omeprazole.

4.  Part 4 presents a summary of the safety data from the OTC and select
    prescription (R~x~) clinical trials

5.  Part 5 provides an overview of the OTC Ome-Mg clinical program.

6.  Part 6 summarizes the efficacy data from the two pivotal clinical
    trials.

7.  Part 7 summarizes the data from the four consumer understanding and
    behavior trials.

8.  Part 8 presents an overall summary of consumer understanding and
    behavior studies.

9.  Part 9 contains a statement of the benefit and potential risk of
    having Ome-Mg available in the OTC setting.

10. Part 10 provides the reference citations.

# Overview of the Briefing Document 

## Introduction

As background, an extensive review of efficacy and safety data for
omeprazole magnesium (Ome-Mg) was presented to Advisory Committee on
October 20, 2000. At this meeting, the Advisory Committee concluded
Ome-Mg may be suitable for management of frequent heartburn in the
over-the-counter (OTC) setting. The Committee voted favorably on the
safety of Ome-Mg and the efficacy of 20 mg data from the 14-day
prevention of frequent heartburn symptoms for 24-hour efficacy studies.
However, the Committee recommended the Sponsor propose new labeling
congruent with the existing efficacy data and with results of actual use
studies.

Working with FDA, we have developed a new label and tested it in Label
Comprehension and Actual Use studies to evaluate how consumers would
likely use the product in an OTC setting. In addition, the following
elements have been agreed to with the Agency as appropriate starting
points for OTC status for Ome-Mg: the dose is 20 mg, the OTC indication
is for the prevention of the symptoms of frequent heartburn for 24
hours, defined as heartburn 2 or more days per week, and the appropriate
dosing of OTC Ome-Mg is a regimen-based use direction.

This briefing document provides a summary of the data and relevant
supporting information that qualifies this new label for the OTC use of
Ome-Mg tablets for prevention of the symptoms of frequent heartburn. It
highlights the critical data from the clinical efficacy and consumer
understanding and behavior program, and safety results from the clinical
program as well as from worldwide prescription (R~x~) clinical trials
and post-marketing surveillance databases to establish suitability of
Ome-Mg for OTC status. It responds directly to Advisory Committee and
FDA feedback to bring the label, efficacy data, and use data into
congruence.

The data presented in this Briefing Document demonstrates the following:

-   Clinically and statistically significant data supporting the
    efficacy of 20 mg Ome-Mg in the prevention of the symptoms of
    frequent heartburn for 24 hours when used over 14 consecutive days

-   14 days is the appropriate self-management regimen duration for this
    product's OTC symptom prevention indication; use beyond that should
    be with the acknowledgment of a learned intermediary

-   The new label enables consumers to appropriately self-select the
    product and use it correctly

-   The use of Ome-Mg in an OTC setting with this new label does not
    pose undue risk to special populations, e.g., those OTC consumers
    who may have undiagnosed gastroesophageal reflux disease (GERD)
    and/or erosive esophagitis (EE) that may require healthcare
    professional supervision and long-term treatment. In fact, the
    evidence suggests use of this OTC product as labeled will allow both
    consumers and physicians to better identify and motivate more of the
    subset of frequent heartburn sufferers to seek medical guidance.

Each of these points has been carefully addressed in the context of the
proposed label, selection of dose and duration of use, and clear warning
language. The consumer understanding and behavior program (Label
Comprehension and Actual Use testing) presented here was conducted to
demonstrate consumers understand the proposed product label,
appropriately self-select this as a product appropriate for use, use the
product according to the label directions, and, importantly, seek
appropriate healthcare professional attention.

The label proposed for OTC status of Ome-Mg is on the following page.

PROPOSED LABEL

BACK CARTON PANEL

+------------------------------------+---------------------------------+
| Drug Facts                         | ***Drug Facts (continued)***    |
+------------------------------------+---------------------------------+
| ***Active ingredient (in each      | **If pregnant or                |
| tablet) Purpose***                 | breast-feeding,** ask a health  |
|                                    | professional before use.        |
| Omeprazole magnesium 20.6 mg       |                                 |
| ..........................Acid     | **Keep out of reach of          |
| reducer                            | children.** In case of          |
|                                    | overdose, get medical help or   |
| (equivalent to 20 mg omeprazole)   | contact a Poison Control Center |
|                                    | right away.                     |
+------------------------------------+---------------------------------+
| ***Uses***                         | ***Directions***                |
|                                    |                                 |
| -   for **prevention** of the      | Adults 18 years of age and      |
|     symptoms of frequent heartburn | older:                          |
|     for\                           |                                 |
|     24 hours                       | -   for prevention of frequent  |
|                                    |     heartburn, swallow 1        |
| -   only for those who suffer      |     tablet\                     |
|     heartburn two or more days a   |     with a glass of water in    |
|     week                           |     the morning                 |
+------------------------------------+---------------------------------+
| ***Warnings***                     | -   take every day for 14 days  |
|                                    |                                 |
| **Allergy alert** Do not use if    | -   do not continue beyond 14   |
| you are allergic to omeprazole     |     days unless directed by\    |
|                                    |     your doctor. If your        |
| **Heartburn Warning. Heartburn can |     frequent heartburn          |
| be a sign of a more serious        |     continues or returns, it    |
| condition.** Notify your doctor if |     could be a sign of a more   |
| you have had heart-\               |     serious condition.          |
| burn for 3 months or longer        |                                 |
| without talking to your doctor.    | -   do not take more than 1     |
|                                    |     tablet a day                |
|                                    |                                 |
|                                    | -   do not chew or crush the    |
|                                    |     tablets                     |
+------------------------------------+---------------------------------+
| **Do not use**                     | Children under 18 years of age: |
|                                    | ask a doctor                    |
| -   with other acid reducers       |                                 |
+------------------------------------+---------------------------------+
| **Ask a doctor before use if you   | ***Other Information***         |
| have**                             |                                 |
|                                    | -   read the directions,        |
| -   any of the following symptoms  |     warnings, and package       |
|     and have not seen a doctor     |     insert before use           |
|                                    |                                 |
| -   frequent chest pain            | -   keep the carton and package |
|                                    |     insert. They contain        |
| -   chest pain with shortness of   |     important information.      |
|     breath; sweating; pain         |                                 |
|     spreading to arms, neck or     | -   store at 25°C (77°F );      |
|     shoulders; or lightheadedness  |     excursions permitted to     |
|                                    |     15-30°C (59-86°F)           |
| -   trouble swallowing food        |                                 |
|                                    | -   avoid product exposure to   |
| -   frequent wheezing,             |     excessive heat and humidity |
|     particularly with heartburn    |                                 |
|                                    | -   protect from moisture       |
| -   unexplained weight loss        |                                 |
|                                    |                                 |
| These may be signs of more serious |                                 |
| conditions. Notify your doctor.    |                                 |
+------------------------------------+---------------------------------+
| **Ask a doctor or pharmacist       | ***Inactive ingredients***      |
| before use if you are taking**     | glyceryl monostearate,          |
|                                    | hydroxypropyl cellulose,        |
| -   warfarin (blood thinning       | hydroxypropyl methylcellulose,\ |
|     medicine)                      | iron oxide, magnesium stearate, |
|                                    | methacrylic acid\               |
| -   phenytoin (seizure medicine)   | copolymer, microcrystalline     |
|                                    | cellulose, paraffin,            |
| -   ketoconazole (prescription     |                                 |
|     antifungal medicine)           |                                 |
+------------------------------------+---------------------------------+
| **Stop use and ask a doctor if**   | polyethylene glycol 6000,       |
|                                    | polysorbate 80,                 |
| -   stomach pain continues or      | polyvinylpyrrolidone, sodium    |
|     worsens                        | stearyl fumarate, starch,       |
|                                    | sucrose, talc, titanium         |
| -   heartburn continues or returns | dioxide, triethyl citrate       |
|     after using this product       |                                 |
+------------------------------------+---------------------------------+
| > every day for 14 days            | ***Questions or comments?***    |
|                                    | Call toll free                  |
+------------------------------------+---------------------------------+
| > Safety Feature-Do not use if     | Distributed By Procter &        |
| > tablet blister unit is open or   | Gamble, Cincinnati, OH 45202    |
| > broken.                          |                                 |
+------------------------------------+---------------------------------+
|                                    |                                 |
+------------------------------------+---------------------------------+
|                                    |                                 |
+------------------------------------+---------------------------------+

## Executive Summary

### Target Population: The Consumer Population with Frequent Heartburn

The target population for OTC Ome-Mg is comprised of consumers with
frequent heartburn, defined as heartburn symptoms two or more days per
week.

Consumers with frequent heartburn are prevalent in the heartburn
population in the U.S. Heartburn occurs daily in approximately 7% to 10%
of the adult population^1-2^, and 2 or more days per week in up to 45%
of consumers with heartburn (approximately 40 million people).^3-4^
Because the symptomatic presentation of GERD or EE may not be
distinguishable from frequent heartburn, a small subset of frequent
heartburn consumers may have undiagnosed medical conditions and need to
be considered in labeling for appropriate use in the OTC setting.

The majority of consumers with frequent heartburn symptoms have seen a
healthcare provider (up to 78%)^2,4^, and they primarily turn to OTC
heartburn remedies to manage frequent heartburn. Most OTC consumers
manage their frequent heartburn symptoms with combinations of OTC
heartburn medications. However, consumer surveys show that a significant
proportion of consumers with frequent heartburn are dissatisfied with
current OTC products, primarily because the medication does not last
long enough.^5^ The OTC products intended to treat episodic occasional
heartburn do not provide the degree of acid control needed in the
prevention of frequent heartburn. Prevention of frequent heartburn
symptoms is the goal for these consumers, rather than constant treatment
of ongoing symptoms, and until now there is no OTC product available
that adequately addresses this need.

### Pharmacology of Omeprazole

The pharmacology of omeprazole makes it ideally suited for the
prevention of frequent heartburn symptoms. Omeprazole irreversibly
inhibits the H^+^/K^+^ ATPase on the secretory surface of the gastric
parietal cell, providing a long-lasting effect in reducing gastric acid
secretion despite its relatively short plasma half-life of one hour.
Resumption of normal gastric acid secretion involves regeneration of the
proton pump, a process that occurs progressively during a period of 3--5
days. While Ome is effective on the first dose, the maximum inhibition
of gastric acid is seen after 3 or more days of dosing.

Therefore, regimen-based therapy will provide maximum prevention
efficacy. Ome-Mg is ideally suited for OTC prevention of frequent
heartburn symptoms, addressing the currently unmet needs of OTC
consumers with frequent heartburn.

The efficacy data presented in this submission are consistent with the
pharmacology of Ome.

### Safety

Omeprazole and Ome-Mg have been shown to have excellent safety profiles.

Ome has been marketed worldwide since 1988 under various trade names in
Europe and was the first proton pump inhibitor (PPI) approved for R~x~
use in the United States in 1989. Omeprazole is one of the most
frequently prescribed medications worldwide, and is currently marketed
in 125 countries. To date, approximately 450 million courses of
prescription therapy have been used, many at doses higher (e.g., more
than 80 mg) than the proposed OTC dose of 20 mg and for long durations
of therapy ranging from 4 weeks to several years.

The dosage form evaluated for OTC status is a tablet consisting of
multiple enteric-coated pellets formulated with Ome-Mg. The tablet form
was chosen for OTC status because the tablet is more resistant to
tampering than a capsule, and therefore more suitable for OTC marketing.
The Ome‑Mg tablet has a similar relative bioavailability to the oral
R~x~ capsule forms of Ome. The tablet dosage form is available in 33
countries worldwide including Australia, Germany, and the United
Kingdom. Ome-Mg was also approved (1999) for OTC status in Sweden, for
the relief of heartburn, in doses up to 20 mg. Because of the similar
bioavailability between Ome and Ome‑Mg, the extensive safety database
for Ome is reflective of the safety profile of Ome-Mg.

Omeprazole has demonstrated a highly favorable safety profile over 15
years of worldwide prescription marketing. There is a substantial amount
of experience with the compound in the treatment of many different
acid-related conditions.

The use of Ome-Mg for the prevention of frequent heartburn is expected
to be safe and well‑tolerated in the OTC setting, based on results from
OTC and R~x~ therapeutic trials and post‑marketing surveillance data.
The summary of these safety data indicate:

-   The safety profile for Ome-Mg-treated subjects is comparable to that
    for R~x~ Ome and placebo. Since the relative bioavailability of
    Ome-Mg is similar to that of Ome, clinical and post-marketing safety
    data for Ome provide evidence of long-term safety supporting the OTC
    proposal.

-   There is no dose-related increase in AE reporting for treated
    subjects during the clinical studies.

-   Serious adverse events (SAEs) are rare and do not occur at a rate
    greater than the background rate in the population treated for
    acid-related disorders.

-   No dose adjustment is necessary in hepatic or renal impairment or in
    individuals characterized as slow metabolizers.

-   Reports of overdosage are rare. Symptoms of overdose are transient,
    and have no serious clinical consequences. Importantly, there are no
    serious clinical sequelae to accidental ingestion by children.

-   There is no evidence that Ome has abuse potential nor is there
    evidence that it potentiates the effects of substances of abuse.

-   There is no evidence that individuals "rebound" with excessive acid
    production after stopping treatment with 20 mg Ome.

-   There are no clinically significant hepatic metabolic drug-drug
    interactions, and risk potential is minimal.

-   The risk of esophageal or gastric cancer in individuals with
    frequent heartburn is very low.

-   This product is not intended for use during pregnancy or nursing.
    The label informs pregnant or nursing women to see a healthcare
    professional prior to use. In the event of unintended use by
    pregnant/nursing women, epidemiology data in women who have taken
    Ome while pregnant shows no increased risk of abnormal fetal
    development.

In summary, Ome has an extensive history of safe use, including patients
in the R~x~ setting exposed to high doses for prolonged periods of time.
Its excellent safety record makes it well suited for OTC status.

### Efficacy

Ome-Mg 20 provides 24-hour prevention of the symptoms of frequent
heartburn in the OTC consumer population with frequent heartburn
(heartburn symptoms 2 or more days per week).

The OTC clinical support consists of two adequate and well-controlled
studies in prevention of frequent heartburn for 24 hours. A total of
3124 subjects are included in the intent-to-treat (ITT) population of
the efficacy studies, described in more detail in Section 5 of this
document.

The studies evaluated both the 10 and 20 mg doses Ome-Mg, and product
was taken for 14 consecutive days. The 20 mg dose is proposed for OTC
status due to its superior acid suppression and more consistent clinical
efficacy vs. 10 mg. Ome-Mg 20 is more effective than placebo in
preventing heartburn symptoms for 24 hours after the first dose. With
consecutive daily dosing over a 14-day period, Ome-Mg 20 was
significantly more effective than placebo in the prevention of frequent
heartburn.

### Proposed Dose and Duration for OTC Status

Ome-Mg 20 provides more effective and consistent 24-hour acid
suppression than 10 mg. Ome‑Mg is more effective than placebo in
preventing frequent heartburn symptoms for a full 24 hours after the
first dose and when dosed for 14 consecutive days. The pharmacology of
the drug is best suited for regimen-based dosing.

**Dose:** The proposed OTC dose is 20.6 mg Ome-Mg (equivalent to 20 mg
Ome). This is based on the following:

-   The pharmacodynamic data demonstrate that Ome 20 provides a
    pronounced and consistent gastric acid inhibition over 24 hours. The
    magnitude and consistency of this effect is significantly better for
    20 mg over 10 mg (see Section 3.0).

-   Ome 20 has an excellent safety profile. Review of the databases from
    R~x~ clinical trials, post‑marketing surveillance data from nearly
    15 years of marketing history and over 450 million courses of
    therapy worldwide, and from the OTC clinical program confirm the
    safety of this product in an OTC setting. The safety profile of
    Ome-Mg is not different from Ome and the relative bioavailability
    profiles are similar.

-   In the OTC clinical program, Ome-Mg 20 shows efficacy on the first
    dose, last dose, and across 14 days of consecutive dosing, for the
    prevention of heartburn for 24 hours in the specified population of
    consumers with frequent heartburn. This efficacy was always
    directionally better than 10 mg, and in some cases statistically
    greater as well, even though studies were not powered to detect a
    statistical difference.

**Duration:** Because the pharmacology of omeprazole (onset to action
profile, long duration of action) matches very well with the frequency
of symptoms in the target population, it is proposed that the product be
labeled with instructions to use for consecutive days. The proposed
duration of consecutive days dosing for the OTC label is 14 days. The
basis for adopting this 14-day use instruction in the OTC labeling is
well substantiated.

-   Two well-controlled pivotal clinical studies show clinically and
    statistically significant efficacy in the prevention of frequent
    heartburn symptoms for the 14-day period. These clinical studies
    (Studies 171 and 183), conducted in the OTC target population,
    demonstrated statistically significant prevention of heartburn
    symptoms for 24 hours on the first dose, the last dose, and across
    all 14 days. These results are consistent with existing data on Ome
    amelioration of heartburn symptoms within 14 days in R~x~ patient
    populations.^53-63^

-   Fourteen days duration is the label instruction that has been shown
    to provide consumer understanding and compliance. The Actual Use
    study demonstrated the most consumers can and do follow the label
    directions, including the directions to take Ome-Mg every day, and
    only for 14 days. Only 34 out of 758 people recorded that they took
    more than 14 doses, and 41% of those contacted a healthcare provider
    during the trial.

-   Fourteen days of therapy is an appropriate duration, after which, if
    symptoms continue or return, people should see a doctor. It has been
    shown in a 1999 study^62^ that continuation or rapid return of
    symptoms following 14 days of Ome 20 is a good indicator of the need
    for continued therapy, best provided with physician oversight. The
    failure to respond to 14 days of therapy serves, in effect, to help
    the right people recognize the need for physician attention.
    Directing individuals whose symptoms continue or return to contact
    their doctor is consistent with medical practice guidelines which
    call for further attention if symptoms continue or return after PPI
    therapy. The proposed labeling includes multiple messages for such
    individuals to seek physician involvement. In the Actual Use study,
    subjects understood the need to see their healthcare provider about
    their heartburn. In the 3 months of the trial, two-thirds as many
    subjects saw a healthcare provider as had done so in the prior year
    (34% versus 48%), and 20% of those who had never seen a healthcare
    provider about heartburn did so for the first time while using the
    labeled product.

-   Fourteen consecutive days use of omeprazole is a conservative
    approach for application, to the OTC setting, guidelines of the ACG,
    AFFP, and ACP for the management of patients with frequent heartburn
    symptoms. All these guidelines indicate that a PPI is an appropriate
    empiric course of therapy in the management of patients with
    frequent heartburn symptoms.^52,66-68^ Some do not specify a
    duration^52,66-68^ or specify 14 to 28 days.^65^ Labeling OTC
    omeprazole for a 14-day regimen adopts a conservative course of
    therapy a physician might prescribe, and as such, is appropriate
    labeling for PPI use in the OTC setting. This 14-day regimen is also
    consistent with the longest duration allowed for as necessary use of
    current OTC heartburn medications without physician direction.

-   A longer duration of regimen was considered and judged to be
    unwarranted in the OTC setting. The primary reason identified for
    considering a longer duration regimen was therapy of subjects within
    the target population who may have more serious conditions that the
    product is not indicated for, e.g., erosive esophagitis (about 10%
    of frequent heartburn sufferers may have EE). Castell, *et al.*
    1996, shows that, of the people with diagnosed EE who were healed
    with 28 days of Ome 20, 74% were already endoscopically healed after
    14 days. It is, therefore, inappropriate to label for a longer
    treatment regimen than is necessary to provide prevention of
    frequent heartburn symptoms for 24 hours across the entire target
    population in order to achieve more complete healing in a small
    subset. A longer duration regimen would overmedicate the substantial
    majority of the target population. The small subset would be better
    served by seeking the involvement of a physician as directed by
    product labeling.

-   Finally, we have carefully considered a label scenario allowing for
    multiple 14-day courses of therapy in a year. We have concluded the
    label direction for one 14-day course and contact your doctor if
    symptoms persist or return is the appropriate direction. This avoids
    the confusion, which would result for consumers if options for
    further cycles of therapy were included in the label directions. The
    proposed label provides a clear and understandable message that
    would be repeated with each subsequent re-purchase and offers the
    highest probability to get those whose symptoms continue or return
    to contact a doctor rather than continuing on their own.

In summary, the 14-day consecutive use instructions are well supported
by the OTC clinical data, OTC label compliance data, conservative
application of medical guidelines to the OTC setting, relevant R~x~ data
and literature as well as consideration for subpopulations. Clear
instructions for physician contact if symptoms continue or return
flowing 14 days is consistent with medical practice and is the most
prudent labeling. This labeling provides for safe and efficacious
unsupervised use and directs those who may be at risk of a more serious
condition to contact their doctor promptly following an appropriate
period of use.

### Consumer Label Understanding and Actual Product Use

The consumer behavior and understanding of product use was evaluated via
two label comprehension studies, a de-selection trial, and an Actual Use
trial. This program of studies established the compliance with label
directions and use of the product in an unsupervised setting. Specific
objectives of the program established whether consumers understood the
population for which the product was best suited (self-selection on
frequency of heartburn and understanding of label warning language),
whether consumers understood when and how to take the product (1 tablet
per day, 14 consecutive doses), and whether consumers understood when to
contact a healthcare provider (in response to specific warning language
or when frequent heartburn returned before taking additional product).

Across studies, consumers demonstrated a good understanding of the label
in regard to the product's intended use, when to use the product, when
not to use the product, and when to seek medical attention.

The Actual Use study determined consumer adherence to the label use
directions under conditions of actual use. Self-selection and consumer
compliance with each of the three label use directions was examined: (1)
whether subjects took no more than one tablet per dose; (2) whether they
took no more than one tablet per day; and (3) whether they adhered to
the 14‑day regimen direction. The results of the Actual Use study are
summarized as follows:

-   96% of subjects took no more than 1 tablet per dose; among 10830
    dosing occasions, 99% involved only one tablet.

-   91% of subjects took no more than 1 tablet per dosing day; among
    10743 dosing days, 98% involved no more than one tablet.

-   79% of subjects were compliant with study use directions to use 14
    doses in a 14-day period (as defined in the protocol, 11--14 doses
    in an 11--17 day period) or to contact a healthcare provider if more
    than 14 doses were taken.

-   9% of subjects took fewer than 11 doses

-   9% of subjects took 14 doses in 18 or more days

-   Only 5% (34 subjects) of subjects recorded that they exceeded 14
    doses during the trial, and, of these, 41% (14 subjects) contacted a
    doctor during the trial per label direction. Overall, 29/34 subjects
    (85%) had talked to a doctor about heartburn before, during or
    shortly after the trial.

-   Thus, only 5 of 758 subjects in the trial used more than 14 doses of
    Ome-Mg without seeking healthcare provider consultation.

Thorough review of the consumer understanding and behavior program
demonstrates that the proposed label is understood, and results in
appropriate behavior from the intended population.

### Risk and Benefit of Ome-Mg in the OTC Setting

This submission establishes that Ome-Mg is safe, effective, and suitable
for prevention of the symptoms of frequent heartburn over 24 hours in an
OTC setting. The pharmacodynamic profile of Ome provides 24-hour control
of gastric acid production, making it an ideal candidate for the
prevention of frequent heartburn.

Ome-Mg provides a clear and unique benefit to OTC consumers with
frequent heartburn over currently existing therapies. Specifically, for
consumers with heartburn two or more days a week, one 20 mg dose taken
daily provides 24-hour frequent heartburn prevention. Statistically and
clinically relevant efficacy is observed on the first day of dosing, on
the last day of dosing, and throughout 14 days of consecutive daily
dosing.

Omeprazole has been widely prescribed since 1988 for a broad spectrum of
acid‑related disorders. Since its introduction, Ome has been approved in
over 125 countries and over 450 million courses of therapy have been
prescribed. The long history of Ome safety and the demonstration of
effectiveness in the target OTC consumer population confirm the
suitability of OTC Ome at a dose of 20 mg.

Ome-Mg is safe for use in the OTC setting, even in the absence of a
healthcare provider, for the prevention of the symptoms of frequent
heartburn. Subjects who use Ome-Mg according to the label (i.e., for 14
consecutive days) will receive benefit even if they have undiagnosed
GERD or EE.^54^ Some subjects may use Ome-Mg for long periods of time
without physician oversight. This, however, is not a widespread concern:
the literature indicates that a high percentage of subjects with
frequent heartburn consult a physician (up to 78%)^2-4^, and the Actual
Use study showed 65% of subjects had contacted a physician about
frequent heartburn. Risk that such behavior will delay diagnosis and
alter the outcome of a more serious underlying condition is small and
outweighed by the benefits of OTC use.

Further, the label instructs consumers at multiple points to consult a
physician if symptoms return or continue.

This submission establishes that Ome-Mg is safe, effective, and suitable
for prevention of the symptoms of frequent heartburn over 24 hours in an
OTC setting. The pharmacodynamic profile of Ome provides 24-hour control
of gastric acid production, making it an ideal candidate for the
prevention of frequent heartburn.

### The Proposed OTC Label for Ome-Mg

The proposed label is congruent with efficacy data, the target
population, the pharmacology of Ome-Mg and the Actual Use study.

The proposed OTC dose for Ome-Mg is 20 mg. This dose was shown in
efficacy trials to provide clinically meaningful and statistically
significant prevention of the symptoms of frequent heartburn for 24
hours in the target population. In addition, review of the safety data
for Ome 20, gathered over 15 years and 450 million courses of therapy,
show Ome-Mg 20 to be a very safe product for its proposed use.

The indication, for the prevention of symptoms of frequent heartburn for
24 hours, is also supported by the results of the efficacy studies. This
indication is consistent with the pharmacology of Ome. The inclusion of
"...for 24 hours" is intended to reinforce the one-tablet-per-day
regimen and ensures the product is not seen as a "cure" for heartburn.
The term "prevention" has been shown in consumer research to reinforce
that the product works best in preventing frequent heartburn symptoms
from recurring over a 24-hour period. While each dose provides a
clinically meaningful and prevention benefit, Ome-Mg works best when
taken on a regimen basis, providing a distinct benefit to the consumer
with frequent heartburn.

The target population, individuals with frequent heartburn symptoms, is
the population with an unmet need in the OTC setting, is the population
for which omeprazole is appropriate (vs. occasional episodic heartburn),
and is the population tested in both the efficacy and behavioral trials.
The efficacy trials showed that 14 days of Ome-Mg 20 effectively
prevents frequent heartburn in this population. Further, the Actual Use
studies showed that individuals with frequent heartburn readily
self-select this is a product they can use. Ome-Mg is not a product
intended for individuals who treat infrequent heartburn (like H~2~RAs
and antacids), and very few individuals with infrequent heartburn choose
Ome-Mg.

Use directions call for one tablet per day, taken in the morning. This
is consistent with the design of the efficacy studies, and subjects were
highly compliant with this direction in the Actual Use study.

The directions also indicate Ome-Mg should be taken every day for 14
consecutive days. This was tested of the design of the efficacy trials,
and again, subjects were highly compliant with this clear and understood
direction in the Actual Use study. This is the appropriate duration in
the OTC setting, and directs consumers to the healthcare provider at the
earliest time if symptoms persist or return.

If frequent heartburn persists or returns after 14 days of Ome-Mg, they
are directed to consult their physician. This is clearly stated in two
places in the labeling. Subjects in the Actual Use trial understood and
complied with these directions. Risks to those who did not comply are
small, and are outweighed by the benefits of the product.

The label contains warnings regarding use in children, potential
drug-drug interactions, unintended use in consumers who are pregnant or
nursing, and those who might experience general warning signs of
potentially serious conditions that might be mistaken for, or occur
with, frequent heartburn. The pregnancy warning statement on the label
is standard OTC labeling. There is no increased risk in any of these
situations. Further, these statements were understood by and complied
with by study subjects. The general warning symptoms should be
considered for all heartburn medications in the OTC setting.

# Characterization of the Consumer With Frequent Heartburn

It is widely acknowledged that heartburn is commonly experienced,
self-recognizable, and self-treated within the general consumer
population. Antacids have been available for decades as an OTC therapy
for the relief of heartburn and H~2~-receptor antagonists (H~2~RAs) have
been available to the OTC population for at least 7 years for both the
relief and prevention of infrequent, episodic heartburn.

Consumers with frequent heartburn, defined as heartburn two or more days
per week, are prevalent in the heartburn population in the U.S.
Heartburn occurs daily in approximately 7% to 10% of all consumers^1-2^,
and 2 or more days per week in about up to 46% of consumers with
heartburn.^2-4^ Some consumers in the OTC setting may have undiagnosed
GERD or EE, and these consumers need to be considered in labeling for
appropriate use of Ome-Mg in the OTC setting.

The majority of consumers with frequent heartburn have seen a healthcare
provider (up to\
78%)^2-4^, and they primarily turn to OTC heartburn remedies to manage
frequent heartburn symptoms. Most OTC consumers manage their heartburn
symptoms with combinations of OTC heartburn medications. However,
consumer surveys show that a significant proportion of consumers with
frequent heartburn are dissatisfied with current OTC products, primarily
because the medication does not last long enough and it does not
completely prevent heartburn.^5^ Prevention of frequent heartburn
symptoms is the goal for these consumers. No OTC heartburn product
currently addresses this need.

OTC Ome-Mg is intended for a population of consumers who experience
frequent heartburn sumptoms. To fully understand the consumer with
frequent heartburn and medication and health care utilization practices
in this population, the Sponsor has conducted a number of qualitative
and quantitative research studies aimed at understanding the beliefs,
habits, and practices of the OTC remedy consumer with frequent heartburn
symptoms.

Collectively, these data characterize the population of consumers with
frequent heartburn.

## The Frequent Heartburn Population

Frequent heartburn is common in the US population: approximately 40
million people experience heartburn symptoms 2 or more days per
week.^1-4^

**Prevalence:** In the US, an estimated 50% of the total population
experiences heartburn, and of those who report heartburn, up to 46%
experience heartburn symptoms 2 days per week or
more.^2-7,12-16,18-21,24^

**Demographics**: Slightly more women (58%) than men report frequent
heartburn.^2,10^ While heartburn can occur at any age, the mean age for
a consumer with frequent heartburn is\
45--50 years^1-3,6-8,10,12,16^, and heartburn does have a slight
tendency to increase with age. According to a United States (U.S.)
survey conducted in 1995 by Nielsen^5^, geographic location, marital
status, family status (children), educational level, job type and level,
and socioeconomic status all play a role in the tendency to develop
heartburn.

**Frequency:** Figure 2.1 shows the frequency of all heartburn episodes
in a 1997 survey of a representative U.S. adult OTC heartburn population
who were asked to recall their heartburn symptom occurrence over the
past 12 months.^3^

[]{#__RefHeading___Toc9124670 .anchor}Figure 2.1\
Frequency of Heartburn in the United States Heartburn Population
(1997)^3^

######### ![](media/image1.wmf) {#section .unnumbered}

**Duration:** Overall, consumers with [frequent]{.underline} heartburn
have had a long history with heartburn.^8, 12,23-24^ According to a 2000
survey by the National Heartburn Alliance, 56% of consumers report
frequent heartburn for five or more years, 40% report experiencing
frequent heartburn for 1--4 years, and the remaining 4% report
experiencing frequent heartburn for less than a year.^8,12^

**Pathophysiology:** Consumers with frequent heartburn have been shown
to have increased esophageal mucosal acid exposure.^14^ However,
frequent heartburn symptoms are not completely correlated with
pathologic sequelae. A prospective study assessed consumers with
frequent heartburn \[of long duration (mean 11 years), moderate severity
(70% of the population) and frequent occurrence (4--7 times per week)\]
whom had never been evaluated by a physician. In this study, erosive
damage was observed in less than 50% of the population and was primarily
grades I/II.^23^ This finding (that long term, frequent heartburn is not
necessarily associated with severe inflammatory damage) is confirmed in
other published epidemiologic observations.^24-26^

## Medication Habits and Practices of the Frequent Heartburn Population

**Prevalence of Medication:** More than 86% of individuals with frequent
heartburn report using OTC heartburn medication.^3^ Nearly all OTC
medication users need to take multiple courses of antacids and/or OTC
H~2~RAs to achieve control of frequent heartburn, especially for 24
hours.

### How Consumers Manage Frequent Heartburn^12^ {#how-consumers-manage-frequent-heartburn12 .Figure-Heading}

-   80% use antacids

-   48% use OTC H~2~RAs

> **--** 26% use OTC H~2~RAs ≥ 4 days per week

-   47% medicate ≥ 2 days in a row

-   55% take medication preventatively

-   58% have spoken with a physician about heartburn

-   34% use a prescription medication

**Frequency of Medication**: As shown from IMS marketing information in
Figure 2.2, the consumers who experience frequent heartburn account for
the majority of the OTC heartburn product usage.

[]{#__RefHeading___Toc9124671 .anchor}Figure 2.2\
Volume of OTC Heartburn Product Use by Frequency of Heartburn\
(All OTC Users Past 12 months)

> ![](media/image2.wmf)

Consumers with frequent heartburn self-medicate frequently during the
day, using the full complement of available OTC heartburn medications,
in an effort to prevent continuing occurrence of frequent heartburn.^12^
In fact, consumers with frequent heartburn quantify the frequency of
their heartburn by the number of days on which they need to dose as well
as the number of days on which they experience heartburn. In one study,
more than 75% of the population reported taking OTC medications to
manage frequent heartburn, even though most (65%) had been to the
doctor.^2^

**Satisfaction with OTC Medications:** Only 19% of consumers with
frequent heartburn experience complete satisfaction with their current
OTC therapeutic options.^7^ This may account for widespread use of
multiple medications during the course of the day to manage frequent
heartburn.^7,12,20,22^

Antacids provide acid neutralization for only a few hours, and the 8--12
hour duration of action of OTC H~2~RAs falls short of the longer
duration consumers with frequent heartburn require. Several studies show
that consumers develop a tolerance for H~2~RAs within a short period of
time, thereby rendering therapy less effective for these
consumers.^9,69^ Tolerance has not been shown to develop with long-term
use of PPIs.^70^

## Medical Utilization Patterns of the Frequent Heartburn Population

The majority of consumers with frequent heartburn symptoms see a
healthcare provider about heartburn: about up to 78% of consumers with
frequent heartburn are under the care of a physician for frequent
heartburn.^2,7-8,10,12,16-17,27-34^ In general, consumers with frequent
heartburn are four times more likely to have seen a physician than the
general population.^2^ Most consumers with frequent heartburn see their
primary care physician (62%) versus a specialist: 16% report seeing a
gastroenterologist and 2% report seeing a cardiologist^16^, while 30% of
consumers with frequent heartburn report also consulting a
pharmacist.^3^

Of those consumers with frequent heartburn who see a physician, 71%
report seeing the physician more than once per year.^7,12^

However, even though consumers with frequent heartburn symptoms often
see a physician, heartburn was most frequently a secondary presentation
at the office visit, confirmed through both surveys of health care
professionals^11^ and consumers with frequent heartburn.^12,16^ Further,
the majority of consumers with frequent heartburn symptoms consider this
to be their least important health problem, or not as important as other
health issues^12^, which helps explain the propensity for heartburn to
be discussed as a secondary presentation.

## Continuing Health Care Utilization Patterns

During the H~2~RA R~x~-to-OTC switch process it was hypothesized that
consumers would stop seeking medical attention for heartburn, and that
diagnosis of potentially more serious underlying conditions would be
delayed. Andrade *et al.*^35^ followed 200 patients with acid-related
conditions before and after the switches, and saw no change in the
overall number of doctor visits. A second study was conducted by Shaw
*et al*.^36-37^ in 3400 OTC consumers in 1993 (pre-switch) and again in
1997 (after the switch by several years), and again found no change in
the average number of doctor visits for acid-related conditions. A third
study among administrative claims for 7 million patients from 1995--1998
(MedStat Marketscan Database) noted an increased number of doctor visits
for acid-related conditions.^38^ These data from the H~2~RA switch era
may give an indication and reassurance that the already-prevalent
behavior of consumers with frequent heartburn to consult the physician
will not change with Ome-Mg in an OTC setting.

## Professional Recommending Patterns

A Professional Habits and Practices study was conducted in 1998 among
250 primary care physicians, 150 gastroenterologists, and 181
pharmacists.^11^ Primary care physicians noted that approximately 13% of
their weekly patients were seen for heartburn (about 16 patients a
week), while the gastroenterologists reported 25% of all patients per
week were seen for heartburn (about 20 patients per week). Both
professional groups noted they tended to see the same heartburn patients
3 to 4 times a year. Pharmacists report counseling about 10 patients per
week about heartburn and heartburn remedies.

Various surveys report that 26% to 50% of the adult heartburn population
receive a prescription for heartburn while 10% to 45% received an OTC
recommendation along with a prescription and 13% received a
recommendation for OTC therapy only.^3,7,11-12,28,30^ About 27% received
recommendation of lifestyle modification.^3,11-12^ Current physician
guidelines for ongoing management of symptomatic reflux have as their
stated objective symptomatic management. Several call for empiric
therapy with acid-reducing agents in the OTC setting, and, if symptoms
can be adequately managed, no further testing or therapy is
required.^52,64-68^

## Heartburn Treatment Guidelines 

In recent publications and reviews of guidelines for management of
frequent heartburn and GERD, the stated primary goal of therapy is
prompt and effective symptom relief.^52,64-67^ For typical uncomplicated
frequent heartburn, an initial trial of empiric therapy with a full‑dose
proton pump inhibitor is generally recommended, as this is considered
the best chance for symptomatic relief.^52,65^ If empricial therapy is
unsuccessful or warning signs are present, further diagnostic testing
should be considered.

The proposed OTC label for Ome-Mg is consistent with these
recommendations, and provides an initial OTC course of therapy, which
will serve to establish whether symptoms are associated with an
acid‑related condition. A 1999 study^62^ in GERD subjects showed that
successful symptom management after 2 weeks with 20 mg of Ome was
correlated with a favorable long-term outcome (p \< 0.0001): 33% of
subjects who responded to 14 days of Ome 20 required no further
treatment over the course of a year and conversely, 24% of subjects in
the entire study population who required an initial course of therapy
beyond 2 weeks tended to require ongoing maintenance treatment; 68% of
subjects who responded to 14 days of Ome 20 required 3 or fewer 14-day
courses of therapy over a year to control frequent heartburn. In
addition, the proposed label clearly directs consumers to consult a
physician if heartburn persists or returns after 14 doses.

## Overall Summary

In summary, consumers with frequent heartburn, defined as heartburn
symptoms two or more days per week, are prevalent in the heartburn
population in the U.S. These consumers are quite knowledgeable about
their heartburn: the majority has been to see their physician about
frequent heartburn symptoms and many have had a prescription for
heartburn at some point. Most OTC consumers manage their heartburn
symptoms with combinations of OTC heartburn medications, although
without total satisfaction in heartburn resolution. These consumers
primarily seek an OTC remedy for adequate frequent heartburn resolution,
and even with frequent physician consultation often receive an OTC
recommendation.

# Clinical Pharmacology of Omeprazole 

Ome-Mg has a pharmacologic profile suited for effective prevention of
frequent heartburn. Ome-Mg has a long duration of action, providing
long-lasting effects for more than 24 hours, and highly effective acid
suppression at steady-state (within 5--7 days of consecutive dosing).
These are the two most important factors in effective prevention of
frequent heartburn.

Omeprazole has a very specific action at the gastric parietal cell. Ome
is a proton pump inhibitor (PPI) that inhibits gastric acid secretion by
irreversible specific inhibition of the H^+^/K^+^ ATPase enzyme at the
secretory surface of the gastric parietal cell. In order to exert an
effect, Ome must enter the acidic compartment of the parietal cell.^39^
In this very acidic environment, Ome (a weak base) is protonated and
transformed to the active sulphenamide inhibitor. This protonation and
conversion can only take place at a significant rate at pH \< 2. Only
the acidic milieu of the parietal cell in the gastric mucosa meets this
requirement; proton pumps in other locations (i.e., the colon and
kidney) are not sufficiently acidic to promote protonation to the active
form of the drug. Acid secretion returns when new parietal cells become
active, a process that takes approximately 3--5 days.

The plasma elimination half-life (t~½~) of less than 1 hour shows a
rapid elimination of the drug, and the absence of Ome in the urine or
feces indicates complete metabolism. Omeprazole is metabolized by two
different cytochrome P450 (CYP) isoforms, CYP2C19 (responsible for about
80% of the total metabolism) and CYP3A4.^40-41^ There is a small subset
of the population that lacks CYP2C19 (approximately 15% of Asians and 3%
of Caucasians) and are known as "slow" metabolizers who still metabolize
Ome but at a slightly slower rate.^42^ However, even at this slower
rate, the plasma half life is still \< 2 hours. Thus, Ome clears rapidly
from the plasma in all subjects.

Omeprazole is completely absorbed after oral administration. Food,
antacids, and H~2~RAs have no clinically meaningful influence on the
extent of Ome absorption.^40,43-44^

Ome-Mg is a magnesium salt version of Ome that permits tablet
formulation. Ome-Mg dissociates rapidly in water to form Ome and
magnesium: a 20.6 mg dose of Ome-Mg is the same as a 20 mg dose of Ome.

As shown in Table 3.1, Ome-Mg has a similar bioavailability profile to
the commercially available Ome capsules. When Ome 20 was compared to
Ome-Mg 20, relative areas under the curve were comparable within a
fairly tight range.

+--------------------+------------+-----------+-----------+-----------+
| ### Tab            |            |           |           |           |
| le 3.1 Ratios of G |            |           |           |           |
| eometric Means and |            |           |           |           |
|  95% Confidence In |            |           |           |           |
| tervals for AUC~0\ |            |           |           |           |
|  ~Subjects with Co |            |           |           |           |
| mplete Pharmacokin |            |           |           |           |
| etic Data {#table- |            |           |           |           |
| 3.1-ratios-of-geom |            |           |           |           |
| etric-means-and-95 |            |           |           |           |
| -confidence-interv |            |           |           |           |
| als-for-auc0-subje |            |           |           |           |
| cts-with-complete- |            |           |           |           |
| pharmacokinetic-da |            |           |           |           |
| ta .Table-heading} |            |           |           |           |
+--------------------+------------+-----------+-----------+-----------+
|                    |            | **95%     |           |           |
|                    |            | C         |           |           |
|                    |            | onfidence |           |           |
|                    |            | Limits**  |           |           |
+--------------------+------------+-----------+-----------+-----------+
| **\                | **\        | Lower     | Upper     | **        |
| Treatments^a^**    | Ratio**    | Limit     | Limit     | Pairwise\ |
|                    |            |           |           | *p*       |
|                    |            |           |           | -Values** |
+--------------------+------------+-----------+-----------+-----------+
| Ome-Mg 20 (X)\     | 1.042      | 0.980     | 1.108     | 0.188     |
| to Ome 20(Y)       |            |           |           |           |
+--------------------+------------+-----------+-----------+-----------+
| ^a^ For each pair  |            |           |           |           |
| of treatments, the |            |           |           |           |
| ratios and         |            |           |           |           |
| confidence limits  |            |           |           |           |
| represent X/Y.     |            |           |           |           |
+--------------------+------------+-----------+-----------+-----------+

## Inhibition of Gastric Acid Secretion

Following single oral doses of 20 to 80 mg Ome suspension in buffered
sodium bicarbonate, pentagastrin-stimulated gastric acid secretion is
rapidly and dose-dependently inhibited (Figure 3.1).^46^ Ome begins to
have an effect on gastric acid secretion in as soon as 1 hour. Other
studies have shown that Ome dose-dependently inhibits basal acid
secretion, as well as acid secretion induced by other stimuli, such as
histamine, modified sham-feeding, and peptone, with a similar
efficiency.^47-48^ This finding was expected, because Ome acts at the
final step in the acid secretion process and therefore inhibits gastric
acid secretion equally effectively and independent of stimulus.

[]{#__RefHeading___Toc9124672 .anchor}Figure 3.1\
Effect of Single Oral Doses of Omeprazole Suspension on Pentagastrin
Stimulated\
Gastric Acid Secretion in Healthy Subjects (n=6)

![](media/image2.wmf)

[]{#_Ref478176761 .anchor}Ome has a long duration of action: more than
24 hours following a single dose, since parietal cells turn over in
about 3--5 days. Both 20 mg and 40 mg single doses of Ome produced a
marked inhibition of gastric acid secretion 2 hours after dosing, and
the degree of acid inhibition then gradually decreased over the next 3
days (Figure 3.2).^46^ With a single 20 mg dose, inhibition was not
significantly different from placebo by Days 3 and 4. A 40 mg dose of
Ome displayed a small but statistically significant inhibition of acid
secretion at Day 3, but by Day 14 returned to baseline levels. The acid
inhibitory effect of Ome lasts longer than circulating plasma levels.
The return of acid output to baseline level is linear in contrast to the
exponential elimination of drug from plasma.

Figure 3.2\
Duration of Action of Two Different Single Oral Doses of Omeprazole
Suspension Estimated by Repeated Measurements of Pentagastrin Stimulated
Gastric Acid Secretion\
in Healthy Subjects (n=6)

![](media/image3.wmf){width="5.75in" height="3.192361111111111in"}

[]{#_Ref478176857 .anchor}The effect of repeated daily doses of Ome on
gastric acid secretion has been studied in both healthy subjects and
duodenal ulcer patients in order to find a clinically relevant
dose.^49-50^ Each dose of Ome (5 mg, 10 mg, 20 mg, 30 mg, or 40 mg) was
given to the patients in a randomized order for 5--7 days, a sufficient
time to reach steady-state suppression of gastric acid secretion.
Pentagastrin‑stimulated gastric acid secretion was measured 6 hours and
24 hours after the last dose (Figure 3.3).^49-50^

From this data, it is clear that 20 mg provides a stronger and more
consistent effect than 10 mg Ome.

Figure 3.3\
Individual Values for Percentage Reduction of Pentagastrin Stimulated
Gastric Acid Secretion Measured Both 6 and 24 Hours After the 5^th^ Dose
of Omeprazole in Healthy Subjects (n=8)

![](media/image5.wmf){width="5.24375in" height="3.1881944444444446in"}

[]{#__RefHeading___Toc9124676 .anchor}Figure 3.4\
The Inhibitory Effects of 1 Week of Treatment with\
Different Daily Doses of Ome on the 24-Hour Intragastric Acidity^71^

![](media/image6.png){width="5.694444444444445in"
height="3.747916666666667in"}

[]{#__RefHeading___Toc9124678 .anchor}Figure 3.5\
Dose Response Curve for Repeated Once Daily Doses of Omeprazole

![](media/image7.png){width="3.4868055555555557in"
height="2.982638888888889in"}

Each Point Represents Reduction in Mean Peak Acid Output in Healthy
Subjects (n=6).\
The Curve Is Obtained by Using an Extended Least Squares Non Linear
Regression Analysis

Figures 3.3 and 3.5 show that once daily treatment with 5 mg Ome for 5
days produced a minimal effect. Figures 3.3 and 3.4 show that a 10 mg
dose of Ome did not produce a consistent inhibition of gastric acid
secretion in all patients. The variation in effect for the 10 mg Ome was
substantial, ranging from 0% to 60% inhibition at 24 hours after the
last dose, and follows a 24‑hour pattern similar to placebo. In
contrast, Ome 20 showed marked 24‑hour acid suppression after 1 week of
therapy.

All 3 figures show a daily dose of 20 mg Ome produces a markedly
stronger and more consistent inhibition than the lower doses, but not a
complete blockade of gastric acid secretion over the 24‑hour dosing
interval (Figure 3.3).

The pharmacokinetic and pharmacodynamic profile of Ome-Mg makes it
uniquely suited for prevention of frequent heartburn for 24 hours in the
OTC setting. The proposed dose of 20 mg is the minimal dose with
consistent long-lived acid suppression, providing maximal efficacy in
this population. Further, 14 days is a suitable period of time for
long-term therapy in the OTC setting, since maximum effect is attained
within 5--7 days and maintained throughout therapy.

# Summary of Safety

Omeprazole has an excellent safety profile as established by more than
15 years R~x~ history in the U.S. (both post-marketing surveillance and
clinical trial experience). Since its introduction, Ome has been
marketed through prescription in 125 countries. An estimated 450 million
courses of patient therapy have been prescribed through June 2001, at
daily doses ranging from 10 to 360 mg, and at therapeutic durations of 4
to 12 weeks, up to several years. The Ome-Mg AE profile from the OTC
clinical trial program showed no difference between Ome-Mg and placebo.
Omeprazole magnesium is approved for prescription use in 33 countries.

## Brief Summary of Safety Information Submitted in the Original NDA 21-229

Initial safety reviews reviewed by the joint NDAC/GDAC (October 2000)
included safety data that were available to AstraZeneca LP (AZLP) and
The Procter & Gamble Company (P&G) through June 30, 1998 from:

-   Clinical trials from the OTC development program with Ome-Mg
    multiple unit pellet system (MUPS) tablets,

-   Clinical trials from prescription Ome capsules,

-   Prescription Ome post‑marketing surveillance data.

The most common AEs reported across clinical trials and post-marketing
surveillance for Ome includes diarrhea, headache, nausea, abdominal
pain, and rash. There are no differences in reporting rates for Ome
relative to placebo, and no dose-related AE correlation. In the
post‑marketing evaluation (through June 1998), from over 300 million
patient courses of therapy, SAEs were found to be associated with
underlying medical conditions.

### Clinical Trials from the OTC Development Program with Omeprazole Magnesium Multiple Unit Pellet System (MUPS) Tablets

The initial clinical program for OTC Ome-Mg consisted of 10 U.S. studies
involving 11,299 subjects. Studies involved 8179 subjects who took Ome
(5040 on Ome-Mg 20, 3139 on Ome-Mg 10) and 3120 subjects who took
placebo. The demographics for the Ome-Mg versus the placebo groups were
similar. The overall extent of exposure for Ome-Mg ranged from a single
dose to taking 30 or more tablets over a 45-day period.

A comprehensive review of all AEs revealed that the most commonly
involved body systems for all treatment groups were Body as a Whole, the
Digestive System, and the Respiratory System. The most commonly reported
AEs were headache, infection, and diarrhea. Omeprazole magnesium had a
similar safety profile to placebo.

No gender-dependent increases in AE reporting were found. No
age-dependent increases in AE reporting were found except for a higher
AE reporting incidence in the age group 12--17 (reported from the Actual
Use studies 003 and 067).

There was no dose-dependent increase in AE reporting for Ome-Mg-treated
subjects in the clinical trials. In these trials, the safety profile of
Ome-Mg 20-, Ome-Mg 10-, and placebo‑treated subjects was similar. The
percentage of discontinuations due to AEs was similar for Ome-treated
subjects (0.5%) compared to placebo-treated subjects (0.6%).

One subject who was randomized to Ome-Mg 20 died. The death was
considered unlikely to be due to study medication.

A total of 28 subjects reported SAEs, with an incidence of 0.4% for
Ome-Mg 10-treated subjects, 0.2% for Ome-Mg 20-treated subjects, and
0.1% for placebo-treated subjects. Only two SAEs were considered to be
possibly or probably due to study medication. These occurred in the
Ome‑Mg 10- and placebo-treated groups. No SAE reported by subjects
receiving Ome-Mg 20 was considered to be possibly or probably related to
study medication. Six additional subjects reported SAEs during the
placebo run-in phase of studies.

The totality of these data strongly suggests that the Ome-Mg tablets
have a safety profile that is consistent with an OTC medication.

### Clinical Trials from Prescription Omeprazole Capsules

Data from clinical trials conducted with the prescription Ome capsule,
in the disease states of GERD, EE and dyspepsia, were pooled and
presented in consideration of OTC Ome-Mg. A total of 5,757 unique
patients were exposed to Ome in these clinical trials: 4,671 in the
Non-US and 1086 in the United States. A total of 1087 unique patients
were exposed to ranitidine and a total of 1,125 unique patients were
exposed to placebo.

An overview of all short-term trials demonstrates that diarrhea and
headache are the most frequently reported AEs for Ome and the placebo
group demonstrated a similar AE profile. Thus for short-term trials
(≤ 12 weeks in duration), Ome has a similar safety profile to placebo.

In long term (\> 12 weeks in duration) clinical trials, the percentage
of patients reporting one or more AEs and the general AE profile was
similar for Ome and placebo. The safety profile for long-term usage of
Ome was similar to the safety profile for short-term usage.

There was no clinically meaningful change in the AE profile for Ome when
evaluations were performed according to age, race, gender, or for dose
and duration of use. Patients discontinued from the clinical trials due
to AEs at a rate lower on Ome than placebo.

The clinical trial data for the Rx indications of GERD, EE and dyspepsia
show that Ome at doses of 10 mg, 20 mg, and 40 mg has a safety profile
similar to placebo. This database includes patients who have taken up to
40 mg of Ome for up to one year. The available safety data therefore
suggests that Ome is safe for OTC use.

### Prescription Omeprazole Post‑Marketing Surveillance Data

A search of the AstraZeneca safety database was conducted and summarized
for reports received and verified on or before June 30, 1998, in which
oral Ome was a medication associated with the report. There were
approximately 300 million patient treatments worldwide up to that time.
A total of 7,344 cases were retrieved which included 15,385 AEs.

The most frequently reported AEs included the following Body Systems:
Body as a Whole -- General Disorders, Gastro- Intestinal System
Disorders, Central and Peripheral Nervous System Disorders, and Skin and
Appendage Disorders. The most commonly reported AEs were diarrhea,
headache, nausea, abdominal pain, and rash. These AEs are consistent
with the current approved labeling for PRILOSEC^^.

Within this review, a total of 287 deaths were noted, 145 of which were
coded as deaths (142) or sudden death (3) and an additional 142 cases in
which death was an outcome but was not coded as an AE. The most reported
AE terms in this group were myocardial infarction, sepsis, cardiac
arrest, hepatic failure, and cardiac failure. Each report dealing with
an outcome of death was reviewed extensively. The common theme in these
cases was that multiple causative factors were present which could have
resulted in the death of the patient. In many other cases not enough
information was received in order to determine the cause of death. A
review of these cases suggests no clinically meaningful trend exists to
establish a cause and effect relationship between Ome intake and an
outcome of death.

A total of 1,750 patients experienced a SAE not resulting in death. The
body systems that were most commonly involved include Body as a Whole --
General Disorders, Gastro-Intestinal System Disorders, Liver and Biliary
System Disorders and Central and Peripheral Nervous System Disorders.
The most frequent SAEs reported were thrombocytopenia, hepatitis,
interstitial nephritis, fever, and drug interaction. The Ome
post-marketing database includes the treatment of patients who were
seriously ill with concurrent underlying medical conditions. The natural
medical history of these conditions was in some instances a contributing
cause of subsequently reported SAEs. In addition, Ome was frequently
used to prevent and/or treat occurrences such as stress ulcers, EE, and
other causes of acute gastrointestinal bleeding in high-risk
individuals.

## Safety Update Report

### Clinical Trial Data

The four-month Safety Update Report (SUR) provided information from four
(4) Ome magnesium clinical trials in an OTC population. A total of 4
U.S. clinical studies involving 7130 subjects are included in this
safety analysis as part of the consideration of OTC Ome-Mg. These
studies involve 4914 subjects who have taken Ome-Mg (2211 on Ome-Mg 20,
2703 on Ome-Mg 10) and 2216 subjects who have taken placebo. Three of
the studies were double-blind placebo controlled studies and the fourth
was an uncontrolled actual use trial.

The four additional OTC clinical trials were conducted by The Procter
and Gamble Company. A total of 4423 subjects in the safety database were
exposed to Ome-Mg for a single dose, and an additional 491 subjects were
exposed to Ome-Mg 10 for up to 4 weeks of treatment duration. Of the
4914 subjects exposed to Ome-Mg, 2211 subjects were exposed to Ome‑Mg 20
and 2703 subjects to Ome-Mg 10. In addition, 2216 subjects were exposed
to placebo.

A comprehensive review of all AEs revealed that in general the most
commonly involved body systems groups were the Body as a Whole, the
Digestive System, and the Respiratory System. In general, and consistent
with data previously reviewed from OTC and prescription clinical trials
and reviews of the worldwide post-marketing surveillance database, the
most commonly reported AEs were headache, diarrhea, and nausea. Ome-Mg
has a similar safety profile to both Ome and placebo.

No gender-dependent increases in AE reporting were found. No
age-dependent increases in AE reporting were found except for a higher
AE reporting incidence in the 12--17 age group (1 report out of 7
subjects in this age group). There was no apparent dose-dependent
increase in AE reporting for Ome-Mg-treated subjects during the
single-dose, double-blind, placebo-controlled clinical trials. In these
trials, the safety profiles of Ome-Mg 20-, Ome-Mg 10-, and
placebo‑treated subjects were similar.

The percentage of discontinuations due to AEs was similar for
Ome-treated subjects compared to placebo-treated subjects. One subject
who was randomized to Ome-Mg 10 died; the death was considered Unlikely
to be due to study medication. A total of 3 subjects reported SAEs
(including the death), all on Ome-Mg 10. All were considered to be
Unlikely due to study medication.

### Post-Marketing Data-- Ome-Mg (MUPS) Tablet Formulation - SUR

The SUR also provided all worldwide serious and non-serious
post-marketed prescription Ome‑Mg MUPS tablet AE information reported to
AZLP in Sweden through December 31, 1999, from countries where the
tablet formulation was marketed. The period from first launch in
February 1998, and up to December 31, 1999, encompasses 11.6 million
patient treatment courses of Ome-Mg (MUPS) tablets. During the same time
period 219 AE reports were notified to AstraZeneca. The most commonly
reported AEs were diarrhea, headache, nausea, and abdominal pain,
consistent with previous reports. There was no evidence to suggest that
the AE pattern for Ome MUPS tablets is different from that of Ome
capsules.

## Updated Safety Information Included in the Resubmission of NDA 21-229

Updated safety data is provided from the P&G Actual Use Study 2001007,
and updated worldwide post-marketing experience with Ome-Mg MUPS tablets
is reported from the time period covering January 1, 2000, through June
30, 2001.

### Clinical Trial Adverse Event Data from P&G Actual Use Study 2001007

Study 007 was a single actual use study involving 758 subjects who
received Ome-Mg 20. A comprehensive review of all AEs revealed that in
general the most commonly involved body systems groups were the Body as
a Whole, the Digestive System, and the Respiratory System. In general,
and consistent with previous reports, the most commonly reported AEs
were headache, diarrhea, pain abdomen, pain and pain back. No particular
AE in any body system was more prevalent in any one of the subgroups
analyzed, i.e. gender, ethnicity, age, or women of childbearing
potential. Subjects over the age of 65 were not susceptible to an
increase in AEs. With the exception of headache, AEs were reported by
less than 4% of the study population, and the majority of AEs were
reported by less than 2% of the study population.

The most frequently reported AE for Ome-Mg 20 was headache, but was not
severe enough to cause discontinuation of therapy. The incidence of
headache is consistent with the Ome capsule safety profile and previous
clinical trial data.

The three discontinuations due to an AE represented 0.4% of the study
population. One SAE resulting in hospitalization occurred during the
treatment period one day after two doses of Ome‑Mg 20 were taken. This
SAE was considered to be unrelated to treatment.

In summary, results from this actual use study demonstrated that the AEs
reported with Ome‑Mg 20 are consistent with reports from Ome and
previous Ome-Mg studies, and are not different than reporting rates seen
with placebo. All AEs were self-limiting, and with the exception of
headache, were reported at a low frequency by subjects.

### Updated Post-Marketing Data -- Omeprazole magnesium (MUPS) Tablet Formulation

The reporting period of January 1, 2000, through June 30, 2001,
encompasses more than 27 million patient treatment courses of Ome-Mg
tablets. A review of reports shows that 109 SAEs among 63 (60 non-fatal
and 3 fatal) patients and 430 non-SAEs among 257 patients were reported
to AstraZeneca.

The five most common AEs reported for non-serious events were consistent
with previous reports and confirm the excellent safety profile of
Ome-Mg: Drug ineffective, Dyspepsia, Dermatitis, Abdominal pain, and
Nausea.

The most common SAEs reported were Dyspnea, Hepatic function abnormal,
Abdominal pain upper, Angioneurotic edema, Dermatitis, Liver function
tests abnormal, Pancytopenia, Stevens Johnson Syndrome, Toxic epidermal
necrolysis (TEN), and Vomiting.

For the reporting period of this safety summary, January 1, 2000 through
June 30, 2001, there continues to be no evidence to suggest that the AE
pattern of Ome-Mg tablets is different from that of Ome capsules. The
collective safety experience of the Ome capsule and the Ome-Mg tablet
strongly suggests Ome has an excellent safety profile and supports the
use of Ome‑Mg when administered to consumers in an OTC population.

## Other Safety Related Issues

### Drug/Drug Interactions

The potential for metabolic drug interactions with Ome (metabolized
primarily by the CYP2C19 pathway) has been systematically studied in a
manner to maximize the ability to detect such an interaction. In the OTC
Ome-Mg clinical program, diazepam, phenytoin, warfarin, and
clarithromycin were labeled as drug interactions until the NDA had been
reviewed. Upon complete assessment of the pharmacology data, the
potential metabolic drug-drug interactions with diazepam and
clarithromycin and Ome are judged to not be of clinical significance.

However, while interactions between warfarin or phenytoin and Ome are
unlikely, the narrow therapeutic window for these drugs leads to the
conservative precaution of listing them on the labeling for Ome-Mg for
OTC use.

Since treatment with Ome will result in an increased intragastric pH
(decreased acidity), there is a potential for either increasing or
decreasing the absorption of drugs that have pH-dependent absorption.
Some of the drugs/compounds that might be expected to exhibit altered
absorption have been tested in studies with Ome in daily doses of 20 mg
or 40 mg. The absorption of amoxicillin, bacampicillin and ethanol was
unaltered, while for digoxin and nifedipine a slight increase in
absorption was observed (10% and 26%, respectively). The effect on
nifedipine did not have any clinical relevance, based on simultaneous
pharmacodynamic measurements. The effect on digoxin was not considered
to have any clinical relevance in the majority of patients. In line with
the results obtained with histamine H~2~-receptor blockers, e.g., a 95%
decreased relative bioavailability of ketoconazole after ranitidine, it
could be predicted that the absorption of ketoconazole and possibly also
itraconazole would be decreased by Ome treatment because of the elevated
pH obtained. Accordingly, results of one study demonstrated that
absorption was decreased by 80% if ketoconazole was administered 6 to 8
hours after a 60 mg dose of Ome. In another study, the absorption of
itraconazole was decreased by 64% if administered after 2 weeks'
treatment with Ome 40 mg daily.

### Unintended Use in Special Populations

#### Pregnancy 

PRILOSEC^®^ (omeprazole) Delayed Release Capsules were first approved
for marketing in the U.S. in 1989. The initial product labeling
regarding use of Ome during pregnancy was based on five non-clinical
studies. Reproductive toxicology studies conducted in rabbits and rats
at doses about 5.6 to 56 times the human dose on a body surface area
basis produced dose related increases in embryo-lethality, fetal
resorptions and pregnancy disruptions in the rabbits and embryo-fetal
lethality and slight, reversible effects on post-natal body weight gain
in the rats. These findings were secondary to maternal toxicity as the
doses used were toxic to the dams of both species. Teratology studies
conducted in pregnant rats and pregnant rabbits did not disclose any
evidence that Ome was teratogenic. At that time, the clinical experience
with Ome was limited. As expected, pregnant women were excluded from
clinical trials and even general exposure information from worldwide
marketed surveillance was limited to a few countries. Based on these
data PRILOSEC^®^ was assigned a Pregnancy Category C.

The sponsor subsequently submitted a supplement that included 16
non-clinical reproductive toxicology studies for prescription Ome. The
new reproductive toxicology studies, not available at the time the
original NDA was approved and the category C assigned, provided a more
complete context in which to interpret the results of the original
studies.

The supplement also included additional clinical information gathered
during the market history of Ome. Information was submitted from
epidemiological studies conducted by three independent groups on the use
of Ome during pregnancy. These three studies were conducted in Sweden,
Canada, and United Kingdom/Italy. The studies jointly included women who
used Ome at some time during their pregnancy, along with matched cohorts
who used H~2~RAs, non‑teratogenic agents, or untreated reference groups.
The three epidemiological studies compared the frequency of congenital
abnormalities among infants born to women who used Ome during pregnancy
to the frequency of abnormalities among offspring of mothers exposed to
H~2~RAs or other control cases.

The studies together represent over 1200 cases of women who were exposed
to Ome during pregnancy (\> 1000 exposed in the first trimester), and
none of the studies indicated an increased risk of adverse pregnancy
outcome, particularly major malformations, among the offspring of women
in the Ome cohorts. These studies have not shown that Ome increases the
risk of abnormalities when administered during the first trimester of
pregnancy and have not shown any effect of Ome on rates of miscarriage,
low birth weight, or pre-term delivery. However, the power of these
studies to identify such differences is limited.

A review of post marketed surveillance reports, including those found in
published literature, resulted in sporadic reports of congenital
abnormalities among infants born to women who took Ome during their
pregnancies. These cases are noted in the currently approved labeling
for the product. There is, however, no cluster of specific anomalies
among these reports that would suggest a syndrome occurring among Ome
exposures at a rate above the rate for these types of malformations
among general populations.

Although the proposed OTC label does not propose Ome-Mg be used in a
pregnant or nursing consumer, if inadvertent use occurred data suggest
there are no additional risks. Therefore, the proposed OTC label
instructions regarding use of Ome-Mge during pregnancy are appropriate:
"If pregnant or breast-feeding, ask a health professional before use."

#### Pediatric/Adolescents

Ome-Mg is not indicated for use in those who are under 18 years of age.
However, in the event that a child ingests Ome there is information
available on the use of Ome in children. In response to FDA's inclusion
of Ome on the list of drugs for which pediatric dosing information would
be medically important, five clinical studies were conducted in
pediatric patients aged 1 month to 16 years. Rare SAEs occurred but none
were considered attributable to Ome by the investigator. No deaths
occurred during these clinical trials. The AE profile for pediatric
patients was similar to the profile seen in adults. Adverse events
outside the safety profile established for Ome in adults appear to
reflect ongoing medical disorders in the patient subjects recruited for
these trials. The drug is handled kinetically in pediatric patients the
same way it is handled in adults.

Ome administered to pediatric patients as intact capsules or sprinkled
in applesauce was generally well tolerated with an AE profile resembling
that in adults. As in adults, AEs of the gastrointestinal body system
such as diarrhea and constipation were the most frequently reported
events. Data do not suggest that there is an increase in AE profile with
an increase in dose. At around puberty the metabolic capacity of human
livers are the same as adults. The data suggests that children 6 years
of age or older have dose/weight adjusted AUC close to the values
reported in adults.

Overall, the safety profile in adolescent and pediatric patients appears
to be favorable and similar to results in adults.

## Overall Safety Conclusion

The clinical trial data for the R~x~ indications of GERD, EE and
dyspepsia show that Ome at doses of 10 mg, 20 mg and 40 mg has a safety
profile similar to placebo. This database includes patients who have
taken up to 40 mg of Ome for up to one year. These data suggest that Ome
is safe for OTC use. The bioavailability of Ome-Mg is similar to Ome,
and AE profile is also similar, supporting the excellent safety profile
for Ome and the use of Ome-Mg in the OTC setting.

Based on an evaluation of the total data on the metabolic drug-drug
interactions between Ome and drugs metabolized via the CYP2C19
microsomal system (e.g., diazepam, phenytoin, and warfarin), clinically
relevant interactions are unlikely to occur for any of these drugs with
daily doses of 20 mg Ome. However, the narrow therapeutic window for
warfarin and phenytoin leads to the conservative precaution of listing
them on the labeling for Ome for OTC use.

Administration of oral ketoconazole or itraconazole with Ome can
decrease the absorption of the antifungal agents. Itraconazole now
includes labeling for decreased absorption with concomitant proton pump
inhibitor use in the prescription labeling. A warning for ketoconazole
is proposed until such time the prescription labeling includes a warning
for the concomitant use with proton pump inhibitors.

Evaluation of information from preclinical studies conducted after the
approval of Ome in the US as well as three epidemiological studies
conducted on the use of Ome during pregnancy and clinical information
gathered during the market history of Ome suggests there is no increased
risk if unintended use occurs. In addition, the data support the
following language on OTC label instructions regarding use of Ome during
pregnancy: "If pregnant or breast-feeding, ask a health professional
before use."

The use of Ome-Mg for the prevention of frequent heartburn over a short
therapeutic duration -- i.e., 14 days -- is expected to be safe and well
tolerated in the OTC population. The information presented suggests that
Ome has a favorable safety profile, which is similar for patients of all
ages with the most common AEs being consistent with current labeling for
the prescription product and with clinical study experience.

# Clinical Program Overview

Two adequate and well-controlled efficacy studies (171 and 183) were
conducted to determine the safety and effectiveness of Ome-Mg in the
prevention of frequent heartburn for 24 hours, over a 14-day dosing
period. In addition, four new consumer research trials were performed
which included 2 Label Comprehension trials (02255 and 12179), 1
De-Selection trial (17859), and 1 Actual Use trial (2001007).

In the pivotal efficacy studies (171 and 183), subjects with heartburn 2
or more days per week (representative of the OTC consumer with frequent
heartburn) were enrolled. Subjects were excluded if they had
physician-diagnosed GERD or EE, or took medications that might interfere
with evaluation of the safety or efficacy of Ome-Mg. Inclusion criteria
focused on past and present heartburn experience. During screening,
subjects must have reported a history of heartburn over the past 30 days
with heartburn occurring at least 2 days per week and which were known
to be at least partially responsive to OTC medications. Continued
participation in the studies required that subjects demonstrate
heartburn on at least 2 days during the 7-day run-in period.

The Actual Use trial (007) was a mall intercept trial that used
supplemental advertising to simulate market conditions. The study also,
with FDA permission, required subjects to purchase study medication
(again, in an attempt to simulate market conditions and the consumer
decision point in the market). There were no restrictions on
participation, although subjects were not permitted to purchase
medication if they were pregnant, less than 18 years of age, allergic to
Ome, or had participated in any prior Use Study for Ome-Mg. All subjects
excluded from the use portion of the trial were allowed to participate
in the self-selection portion of the Actual Use trial.

# Efficacy Program

Omeprazole magnesium's long duration of action and its ability to
inhibit all stimuli of gastric acid secretion suggest that Ome-Mg might
be particularly effective in preventing heartburn for a full 24 hours.
Since maximum effectiveness is attained by Day 5--7 with consecutive
daily dosing, a regimen of 14 days' consecutive use is appropriate in an
OTC setting.

Thus the design of the efficacy trials for prevention of frequent
heartburn utilized the unique pharmacologic profile of Ome-Mg in the OTC
population of consumers with frequent heartburn (heartburn 2 or more
days per week).

## Study Design and Clinical Methods

Both studies were multi-center, double-blind, randomized, double-dummy,
parallel, and placebo‑controlled. Each study tested placebo, and 10 mg
and 20 mg of Ome-Mg for 14 consecutive days of use, determined to be the
appropriate time to establish efficacy for OTC use. The studies were
similar with respect to design, conduct, and data analysis.
Collectively, 3162 subjects were randomized to treatment: 2109 to active
medication and 1053 to placebo.

The studies lasted 5 weeks and had three phases: (1) a 1-week,
single-blind, placebo run-in phase; (2) a 2‑week, double-blind,
treatment phase in which patients were randomized to receive a single
daily dose of either Ome-Mg 20, Ome-Mg 10, or placebo per day; and (3) a
2-week, single-blind, placebo, follow-up phase. Subjects took their
daily dose of study medication each morning.

The proposed OTC dose of Ome-Mg is 20 mg, and results of Ome-Mg 20 are
provided in detail. A summary of the results of Ome-Mg 10 is provided in
Section 6.2.3.

A schematic of the design follows in Figure 6.1.

[]{#__RefHeading___Toc9124680 .anchor}Figure 6.1\
Study Schematic for 14-Day Heartburn Prevention Trials

![](media/image8.wmf)

The primary efficacy variable was: No Heartburn over the previous 24
hours (i.e., Complete Prevention of Heartburn or Heartburn-Free for a
full day). Efficacy was evaluated following the first dose of
medication, on the last dose, and over 14 days of dosing during the
double-blind phase.

Secondary efficacy variables included:

1.  Complete Prevention of Nocturnal Heartburn and Occurrence of No More
    than Mild Heartburn following the first dose of medication and
    across all 14 days of dosing during the double-blind phase, and

2.  Occurrence of No More than Mild Heartburn following the first dose
    of medication and across all 14 days of dosing during the
    double-blind phase.

Occurrence of the first episode of heartburn, of any severity, was also
investigated during a 2‑week, single-blind placebo, follow-up phase.

Each morning subjects (a) rated the most severe episode of heartburn for
the previous 24‑hour period using a 5-point scale, (b) indicated whether
or not nocturnal heartburn was experienced, and (c) recorded information
on use of an antacid (Gelusil^®^), which was provided as a backup
medication to be used at the subject's discretion.

### Statistical Methods

For both studies, a Cochran-Mantel-Haenszel test statistic was used to
compare treatment effects on Day 1 for complete prevention of heartburn
over 24 hours, complete prevention of nocturnal heartburn, and the
occurrence of no more than mild heartburn over 24 hours. A logistic
regression analysis was used to compute odds ratios for each treatment
comparison and to assess treatment-by-center interaction for the primary
efficacy variable. For each endpoint, an Analysis of Variance (ANOVA)
was conducted with each of the three variables to compare treatments
with regard to mean percent of days over the 2-week, double-blind phase
when an event took place. Generalized Estimating Equations (GEE) were
used to assess the same three variables over repeated doses.

### Demographics and Other Baseline Characteristics

Collectively, 3162 subjects were randomized to treatment across 49
centers in Trials 171 and 183. A total of 3124 subjects were included in
the ITT dataset for statistical analysis: 2085 to active medication
(1047 to Ome-Mg 20) and 1039 to placebo. The 38 randomized subjects
excluded from the ITT dataset either did not dose with study medication,
recorded no efficacy data, or were enrolled previously in the same
study.

Table 6.1 provides a summary of demographic and heartburn baseline
characteristics by dose group and trial. Baseline characteristics were
similar across treatment groups and trials. The mean reported baseline
heartburn frequency was 5 days per week, of mild severity.

+-----------+-------------+-------------+-------------+--------------+
| ### Ta    |             |             |             |              |
| ble 6.1 D |             |             |             |              |
| emographi |             |             |             |              |
| c and Oth |             |             |             |              |
| er Baseli |             |             |             |              |
| ne Charac |             |             |             |              |
| teristics |             |             |             |              |
|  (Studies |             |             |             |              |
|  171 and  |             |             |             |              |
| 183) {#ta |             |             |             |              |
| ble-6.1-d |             |             |             |              |
| emographi |             |             |             |              |
| c-and-oth |             |             |             |              |
| er-baseli |             |             |             |              |
| ne-charac |             |             |             |              |
| teristics |             |             |             |              |
| -studies- |             |             |             |              |
| 171-and-1 |             |             |             |              |
| 83 .Table |             |             |             |              |
| -heading} |             |             |             |              |
+-----------+-------------+-------------+-------------+--------------+
| Study     | 171         |             | 183         |              |
+-----------+-------------+-------------+-------------+--------------+
| Chara     | Ome-Mg 20\  | Placebo\    | Ome-Mg 20\  | Placebo\     |
| cteristic | N=523       | N=519       | N=524       | N=520        |
+-----------+-------------+-------------+-------------+--------------+
| Gender    |             |             |             |              |
+-----------+-------------+-------------+-------------+--------------+
| Female    | 297 (56.8%) | 287 (55.3%) | 283 (54.0%) | 293 (56.3%)  |
+-----------+-------------+-------------+-------------+--------------+
| Male      | 226 (43.2%) | 232 (44.7%) | 241 (46.0%) | 227 (43.7%)  |
+-----------+-------------+-------------+-------------+--------------+
| Race      |             |             |             |              |
+-----------+-------------+-------------+-------------+--------------+
| Asian     | 4 (0.8%)    | 7 (1.3%)    | 1 (0.2%)    | 4 (0.8%)     |
+-----------+-------------+-------------+-------------+--------------+
| Black     | 63 (12.0%)  | 57 (11.0%)  | 32 (6.1%)   | 33 (6.3%)    |
+-----------+-------------+-------------+-------------+--------------+
| Caucasian | 401 (76.7%) | 399 (76.9%) | 443 (84.5%) | 445 (85.6%)  |
+-----------+-------------+-------------+-------------+--------------+
| Hispanic  | 48 (9.2%)   | 51 (9.8%)   | 36 (6.9%)   | 33 (6.3%)    |
+-----------+-------------+-------------+-------------+--------------+
| Other     | 7 (1.3%)    | 5 (1.0%)    | 12 (2.3%)   | 5 (1.0%)     |
+-----------+-------------+-------------+-------------+--------------+
| Age       |             |             |             |              |
| (Years)   |             |             |             |              |
+-----------+-------------+-------------+-------------+--------------+
| Mean (SD) | 44.5        | 43.7        | 46.7        | 46.0 (14.14) |
|           | (12.77)     | (13.22)     | (14.22)     |              |
+-----------+-------------+-------------+-------------+--------------+
| Min/Max   | 18--86      | 18--79      | 20--84      | 18--79       |
+-----------+-------------+-------------+-------------+--------------+
| Heartburn |             |             |             |              |
| Frequency |             |             |             |              |
| % of Days |             |             |             |              |
| during    |             |             |             |              |
| Run-In    |             |             |             |              |
+-----------+-------------+-------------+-------------+--------------+
| Mean (SD) | 74.3        | 75.2        | 74.2        | 74.2 (24.19) |
|           | (24.39)     | (24.18)     | (23.57)     |              |
+-----------+-------------+-------------+-------------+--------------+
| ≥ 50%     | 419 (80.1%) | 422 (81.3%) | 426 (81.3%) | 417 (80.2%)  |
+-----------+-------------+-------------+-------------+--------------+

## Efficacy Results

### Primary Efficacy Parameter (Heartburn-Free for 24 Hours)

The primary variable, Heartburn-Free for 24 Hours, was generated on
report of no heartburn (i.e., complete prevention), for the 24 hours
preceding the evaluation.

In each study, a significantly greater percentage of subjects in the
Ome-Mg 20 treatment group were Heartburn‑Free than in the placebo group
after the first dose (*p *\< 0.001), after the last dose (*p *\< 0.001),
and over all 14 doses (*p *\< 0.001).

Day 1

Figure 6.2 displays results of the analyses for the primary efficacy
parameter, Heartburn-Free for a Full Day (No Heartburn over 24 Hours) on
Day 1.

[]{#__RefHeading___Toc9124681 .anchor}![](media/image9.wmf)Figure 6.2\
Percent of Subjects with 24 Hour Prevention of Heartburn --- Day 1

Study 171, the percentage of subjects who were Heartburn-Free for the
full day after the first dose was 49.7% for Ome-Mg 20; 17.2% greater
than placebo. In Study 183, 46.8% of subjects on Ome-Mg 20 were
Heartburn-Free for the full day after the first dose; 14.6% greater than
placebo.

Table 6.3 displays results of the analyses for the primary efficacy
parameter, Heartburn-Free for a Full Day (No Heartburn over 24 Hours) on
Day 1.

+--------------------------+-------------------+-----------------------+
| ### Table 6.3 Analysis o |                   |                       |
| f Primary Efficacy Varia |                   |                       |
| ble No Heartburn over 24 |                   |                       |
|  Hours on Day 1  Intent- |                   |                       |
| to-Treat Subjects {#tabl |                   |                       |
| e-6.3-analysis-of-primar |                   |                       |
| y-efficacy-variable-no-h |                   |                       |
| eartburn-over-24-hours-o |                   |                       |
| n-day-1-intent-to-treat- |                   |                       |
| subjects .Table-heading} |                   |                       |
+--------------------------+-------------------+-----------------------+
| **[Study                 | **Ome-Mg          | **[P                  |
| 171]{.smallcaps}**       | [                 | lacebo]{.smallcaps}** |
|                          | 20]{.smallcaps}** |                       |
+--------------------------+-------------------+-----------------------+
| Heartburn-Free (%)       | [49.7%            | [32.6%                |
|                          | (260/             | (                     |
|                          | 523)]{.smallcaps} | 169/519)]{.smallcaps} |
+--------------------------+-------------------+-----------------------+
| **[\                     | **[*\             | **[Diff in Prop.\     |
| C                        | p*-Value]         | (95%                  |
| omparison]{.smallcaps}** | {.smallcaps}**^a^ | CI)]{.smallcaps}**^b^ |
+--------------------------+-------------------+-----------------------+
| > Ome-Mg 20 vs. Placebo  | **[\<0.0          | [17.2% (11.3,         |
|                          | 01]{.smallcaps}** | 23.0)]{.smallcaps}    |
+--------------------------+-------------------+-----------------------+
| **[Study                 | **Ome-Mg          | **[P                  |
| 183]{.smallcaps}**       | [                 | lacebo]{.smallcaps}** |
|                          | 20]{.smallcaps}** |                       |
+--------------------------+-------------------+-----------------------+
| Heartburn-Free (%)       | [46.8%            | [32.1%                |
|                          | (245/             | (                     |
|                          | 524)]{.smallcaps} | 167/520)]{.smallcaps} |
+--------------------------+-------------------+-----------------------+
| **[\                     | **[*\             | **[Diff in Prop.\     |
| C                        | p*-Value]         | (95%                  |
| omparison]{.smallcaps}** | {.smallcaps}**^a^ | CI)]{.smallcaps}**^b^ |
+--------------------------+-------------------+-----------------------+
| > Ome-Mg 20 vs. Placebo  | **[\<0.0          | [14.6% (8.8,          |
|                          | 01]{.smallcaps}** | 20.5)]{.smallcaps}    |
+--------------------------+-------------------+-----------------------+
| ^a^ *p*-Values for       |                   |                       |
| treatment comparisons    |                   |                       |
| obtained from            |                   |                       |
| Cochran-Mantel-Haenszel  |                   |                       |
| chi-square test with     |                   |                       |
| Investigator as a        |                   |                       |
| stratification variable. |                   |                       |
|                          |                   |                       |
| ^b^ Estimated difference |                   |                       |
| in proportions           |                   |                       |
| (expressed as a percent) |                   |                       |
| and 95% confidence       |                   |                       |
| interval using a normal  |                   |                       |
| approximation.           |                   |                       |
+--------------------------+-------------------+-----------------------+

Over 14 Days Dosing Period

The primary therapeutic gain (difference between Ome-Mg 20 and placebo)
in studies 171 and 183 was seen by Day 6, and remained consistently high
after that time. Figure 6.3 and Tables 6.4 and 6.5 highlight this
pattern for Ome-Mg 20 and placebo. In study 171, most of the rate
increase was realized by Day 4--5 for Ome-Mg 20, and in study 183 most
of the rate increase is realized by Day 6 for Ome-Mg 20.

[]{#__RefHeading___Toc9124682 .anchor}Figure 6.3\
Percent of Subjects with 24 Hour Prevention of Heartburn --- Time Course
Over 14 Days\
Studies 171 and 183

![](media/image10.wmf)

+-------+-------+---------------+-------+---------------+------------+
| ###   |       |               |       |               |            |
| Table |       |               |       |               |            |
|  6.4  |       |               |       |               |            |
| Numbe |       |               |       |               |            |
| r and |       |               |       |               |            |
|  Perc |       |               |       |               |            |
| ent o |       |               |       |               |            |
| f Sub |       |               |       |               |            |
| jects |       |               |       |               |            |
|  with |       |               |       |               |            |
|  no h |       |               |       |               |            |
| eartb |       |               |       |               |            |
| urn o |       |               |       |               |            |
| ver 2 |       |               |       |               |            |
| 4 hou |       |               |       |               |            |
| rs, b |       |               |       |               |            |
| y day |       |               |       |               |            |
|   Stu |       |               |       |               |            |
| dy 17 |       |               |       |               |            |
| 1: In |       |               |       |               |            |
| tent- |       |               |       |               |            |
| to-Tr |       |               |       |               |            |
| eat S |       |               |       |               |            |
| ubjec |       |               |       |               |            |
| ts {# |       |               |       |               |            |
| table |       |               |       |               |            |
| -6.4- |       |               |       |               |            |
| numbe |       |               |       |               |            |
| r-and |       |               |       |               |            |
| -perc |       |               |       |               |            |
| ent-o |       |               |       |               |            |
| f-sub |       |               |       |               |            |
| jects |       |               |       |               |            |
| -with |       |               |       |               |            |
| -no-h |       |               |       |               |            |
| eartb |       |               |       |               |            |
| urn-o |       |               |       |               |            |
| ver-2 |       |               |       |               |            |
| 4-hou |       |               |       |               |            |
| rs-by |       |               |       |               |            |
| -day- |       |               |       |               |            |
| study |       |               |       |               |            |
| -171- |       |               |       |               |            |
| inten |       |               |       |               |            |
| t-to- |       |               |       |               |            |
| treat |       |               |       |               |            |
| -subj |       |               |       |               |            |
| ects  |       |               |       |               |            |
| .Tabl |       |               |       |               |            |
| e-hea |       |               |       |               |            |
| ding} |       |               |       |               |            |
+-------+-------+---------------+-------+---------------+------------+
| **\   | **O   |               | **Pla |               | **\        |
| Day** | me-Mg |               | cebo\ |               | Di         |
|       | 20\   |               | N=    |               | fference** |
|       | N=    |               | 518** |               |            |
|       | 523** |               |       |               |            |
+-------+-------+---------------+-------+---------------+------------+
|       | **N   | **%^b^**      | **N   | **%^b^**      | **%**      |
|       | ^a^** |               | ^a^** |               |            |
+-------+-------+---------------+-------+---------------+------------+
| > 1   | 522   | 49.8          | 517   | 32.7          | 17.1       |
+-------+-------+---------------+-------+---------------+------------+
| > 2   | 520   | 56.3          | 515   | 35.3          | 21.5       |
+-------+-------+---------------+-------+---------------+------------+
| > 3   | 518   | 60.6          | 516   | 34.9          | 25.7       |
+-------+-------+---------------+-------+---------------+------------+
| > 4   | 520   | 65.4          | 515   | 37.7          | 27.7       |
+-------+-------+---------------+-------+---------------+------------+
| > 5   | 520   | 64.6          | 514   | 35.2          | 29.4       |
+-------+-------+---------------+-------+---------------+------------+
| > 6   | 521   | 64.9          | 513   | 41.1          | 23.8       |
+-------+-------+---------------+-------+---------------+------------+
| > 7   | 517   | 65.8          | 514   | 38.1          | 27.7       |
+-------+-------+---------------+-------+---------------+------------+
| > 8   | 520   | 66.5          | 511   | 36.6          | 29.9       |
+-------+-------+---------------+-------+---------------+------------+
| > 9   | 518   | 64.9          | 508   | 40.6          | 24.3       |
+-------+-------+---------------+-------+---------------+------------+
| > 10  | 516   | 62.0          | 510   | 40.4          | 21.6       |
+-------+-------+---------------+-------+---------------+------------+
| > 11  | 512   | 68.0          | 511   | 41.7          | 26.3       |
+-------+-------+---------------+-------+---------------+------------+
| > 12  | 512   | 66.0          | 507   | 39.6          | 26.4       |
+-------+-------+---------------+-------+---------------+------------+
| > 13  | 507   | 70.4          | 497   | 45.5          | 24.9       |
+-------+-------+---------------+-------+---------------+------------+
| > 14  | 482   | 72.0          | 464   | 47.0          | 25.0       |
+-------+-------+---------------+-------+---------------+------------+
| > ^a^ |       |               |       |               |            |
| > N   |       |               |       |               |            |
| umber |       |               |       |               |            |
| > of  |       |               |       |               |            |
| > ITT |       |               |       |               |            |
| > sub |       |               |       |               |            |
| jects |       |               |       |               |            |
| > in  |       |               |       |               |            |
| >     |       |               |       |               |            |
|  trea |       |               |       |               |            |
| tment |       |               |       |               |            |
| >     |       |               |       |               |            |
| group |       |               |       |               |            |
| >     |       |               |       |               |            |
|  with |       |               |       |               |            |
| > n   |       |               |       |               |            |
| on-mi |       |               |       |               |            |
| ssing |       |               |       |               |            |
| > v   |       |               |       |               |            |
| alues |       |               |       |               |            |
| >     |       |               |       |               |            |
| > ^b^ |       |               |       |               |            |
| > Pe  |       |               |       |               |            |
| rcent |       |               |       |               |            |
| > of  |       |               |       |               |            |
| > sub |       |               |       |               |            |
| jects |       |               |       |               |            |
| >     |       |               |       |               |            |
|  with |       |               |       |               |            |
| > No  |       |               |       |               |            |
| >     |       |               |       |               |            |
|  Hear |       |               |       |               |            |
| tburn |       |               |       |               |            |
| >     |       |               |       |               |            |
|  over |       |               |       |               |            |
| > 24  |       |               |       |               |            |
| >     |       |               |       |               |            |
| hours |       |               |       |               |            |
+-------+-------+---------------+-------+---------------+------------+

+-------+-------+---------------+-------+---------------+------------+
| ###   |       |               |       |               |            |
| Table |       |               |       |               |            |
|  6.5  |       |               |       |               |            |
| Numbe |       |               |       |               |            |
| r and |       |               |       |               |            |
|  Perc |       |               |       |               |            |
| ent o |       |               |       |               |            |
| f Sub |       |               |       |               |            |
| jects |       |               |       |               |            |
|  with |       |               |       |               |            |
|  no h |       |               |       |               |            |
| eartb |       |               |       |               |            |
| urn o |       |               |       |               |            |
| ver 2 |       |               |       |               |            |
| 4 hou |       |               |       |               |            |
| rs, b |       |               |       |               |            |
| y day |       |               |       |               |            |
|   Stu |       |               |       |               |            |
| dy 18 |       |               |       |               |            |
| 3: In |       |               |       |               |            |
| tent- |       |               |       |               |            |
| to-Tr |       |               |       |               |            |
| eat S |       |               |       |               |            |
| ubjec |       |               |       |               |            |
| ts {# |       |               |       |               |            |
| table |       |               |       |               |            |
| -6.5- |       |               |       |               |            |
| numbe |       |               |       |               |            |
| r-and |       |               |       |               |            |
| -perc |       |               |       |               |            |
| ent-o |       |               |       |               |            |
| f-sub |       |               |       |               |            |
| jects |       |               |       |               |            |
| -with |       |               |       |               |            |
| -no-h |       |               |       |               |            |
| eartb |       |               |       |               |            |
| urn-o |       |               |       |               |            |
| ver-2 |       |               |       |               |            |
| 4-hou |       |               |       |               |            |
| rs-by |       |               |       |               |            |
| -day- |       |               |       |               |            |
| study |       |               |       |               |            |
| -183- |       |               |       |               |            |
| inten |       |               |       |               |            |
| t-to- |       |               |       |               |            |
| treat |       |               |       |               |            |
| -subj |       |               |       |               |            |
| ects  |       |               |       |               |            |
| .Tabl |       |               |       |               |            |
| e-hea |       |               |       |               |            |
| ding} |       |               |       |               |            |
+-------+-------+---------------+-------+---------------+------------+
| **    | **O   |               | **Pla |               | **\        |
| Day** | me-Mg |               | cebo\ |               | Di         |
|       | 20\   |               | N=    |               | fference** |
|       | N=    |               | 520** |               |            |
|       | 524** |               |       |               |            |
+-------+-------+---------------+-------+---------------+------------+
|       | **N   | **%^b^**      | **N   | **%^b^**      | **%**      |
|       | ^a^** |               | ^a^** |               |            |
+-------+-------+---------------+-------+---------------+------------+
| > 1   | 521   | 47.0          | 520   | 32.1          | 14.9       |
+-------+-------+---------------+-------+---------------+------------+
| > 2   | 524   | 59.5          | 519   | 31.4          | 28.1       |
+-------+-------+---------------+-------+---------------+------------+
| > 3   | 523   | 64.4          | 518   | 34.6          | 29.8       |
+-------+-------+---------------+-------+---------------+------------+
| > 4   | 522   | 64.6          | 516   | 34.1          | 30.5       |
+-------+-------+---------------+-------+---------------+------------+
| > 5   | 519   | 67.8          | 516   | 40.5          | 27.3       |
+-------+-------+---------------+-------+---------------+------------+
| > 6   | 520   | 70.4          | 514   | 40.3          | 30.1       |
+-------+-------+---------------+-------+---------------+------------+
| > 7   | 518   | 70.1          | 514   | 40.1          | 30.0       |
+-------+-------+---------------+-------+---------------+------------+
| > 8   | 519   | 70.5          | 512   | 38.7          | 31.8       |
+-------+-------+---------------+-------+---------------+------------+
| > 9   | 518   | 70.5          | 514   | 39.3          | 31.2       |
+-------+-------+---------------+-------+---------------+------------+
| > 10  | 517   | 70.6          | 511   | 37.8          | 32.8       |
+-------+-------+---------------+-------+---------------+------------+
| > 11  | 516   | 70.9          | 512   | 38.7          | 32.2       |
+-------+-------+---------------+-------+---------------+------------+
| > 12  | 514   | 72.0          | 509   | 39.1          | 33.1       |
+-------+-------+---------------+-------+---------------+------------+
| > 13  | 508   | 76.8          | 499   | 42.1          | 34.7       |
+-------+-------+---------------+-------+---------------+------------+
| > 14  | 478   | 73.0          | 480   | 44.0          | 29.0       |
+-------+-------+---------------+-------+---------------+------------+
| ^a^   |       |               |       |               |            |
| N     |       |               |       |               |            |
| umber |       |               |       |               |            |
| of    |       |               |       |               |            |
| ITT   |       |               |       |               |            |
| sub   |       |               |       |               |            |
| jects |       |               |       |               |            |
| in    |       |               |       |               |            |
| trea  |       |               |       |               |            |
| tment |       |               |       |               |            |
| group |       |               |       |               |            |
| with  |       |               |       |               |            |
| n     |       |               |       |               |            |
| on-mi |       |               |       |               |            |
| ssing |       |               |       |               |            |
| v     |       |               |       |               |            |
| alues |       |               |       |               |            |
|       |       |               |       |               |            |
| ^b^   |       |               |       |               |            |
| Pe    |       |               |       |               |            |
| rcent |       |               |       |               |            |
| of    |       |               |       |               |            |
| sub   |       |               |       |               |            |
| jects |       |               |       |               |            |
| with  |       |               |       |               |            |
| No    |       |               |       |               |            |
| Hear  |       |               |       |               |            |
| tburn |       |               |       |               |            |
| over  |       |               |       |               |            |
| 24    |       |               |       |               |            |
| hours |       |               |       |               |            |
+-------+-------+---------------+-------+---------------+------------+

Another way of looking at efficacy across 14 days of dosing is to
examine the percent of days subjects were heartburn-free. With
consecutive daily dosing, Ome-Mg treated subjects had a significantly
greater percentage of heartburn-free days than did placebo-treated
subjects, as seen in Figure 6.4

[]{#__RefHeading___Toc9124684 .anchor}![](media/image11.wmf)Figure 6.4\
Percent of Days with No Heartburn --- Across 14 Day Dosing Period

### Secondary Parameters

Day 1

The secondary variable, No Nocturnal Heartburn, represents the ability
of Ome-Mg to prevent heartburn at the end of the full day after morning
dosing under conditions favorable to development of heartburn, i.e., a
supine position. The secondary variable, No More than Mild Heartburn,
allows development of heartburn that is easily tolerated (Mild), but
still considers the treatment successful.

Table 6.6 displays the results of the analyses for both secondary
efficacy parameters on Day 1. In general, the results of these secondary
variables corroborated the findings for the primary variable. Ome-Mg 20
was significantly superior to placebo in all analyses with one exception
(No Nocturnal Heartburn following first dose in Study 183).

In Study 171, the percentage of subjects with No Nocturnal Heartburn
following the first dose was 78.4% for Ome-Mg 20, 8.0% higher than
placebo (70.4% with No Nocturnal Heartburn). The difference was
statistically significant. In Study 183, the percentage of subjects with
No Nocturnal Heartburn following the first dose was 77.7% for Ome-Mg 20,
not significantly different from placebo (73.9%).

In Study 171, the percentage of subjects with No More than Mild
Heartburn following the first dose was 81% for Ome-Mg 20, 9.4% higher
than placebo (71.6% with No More than Mild Heartburn) and was
statistically significant. Results of Study 183 were similar. The
percentage of subjects with No More than Mild Heartburn following the
first dose was 81.8% for Ome-Mg 20, 11% higher than placebo (70.8% with
No More than Mild Heartburn), and was statistically significant compared
to placebo.

+------------------------+----------------------+----------------------+
| ### Table 6.6 An       |                      |                      |
| alysis of Secondary Ef |                      |                      |
| ficacy Variables Perce |                      |                      |
| ntage of Subjects with |                      |                      |
|  No Nocturnal and No M |                      |                      |
| ore than Mild Heartbur |                      |                      |
| n on Day 1  Heartburn  |                      |                      |
| Over a Full Day Intent |                      |                      |
| -to-Treat Subjects {#t |                      |                      |
| able-6.6-analysis-of-s |                      |                      |
| econdary-efficacy-vari |                      |                      |
| ables-percentage-of-su |                      |                      |
| bjects-with-no-nocturn |                      |                      |
| al-and-no-more-than-mi |                      |                      |
| ld-heartburn-on-day-1- |                      |                      |
| heartburn-over-a-full- |                      |                      |
| day-intent-to-treat-su |                      |                      |
| bjects .Table-heading} |                      |                      |
+------------------------+----------------------+----------------------+
|                        | **Ome-Mg 20**        | **Placebo**          |
+------------------------+----------------------+----------------------+
| **No Nocturnal         |                      |                      |
| Heartburn^a^**         |                      |                      |
+------------------------+----------------------+----------------------+
| Study 171              | **78.4%^b^**         | 70.4%                |
+------------------------+----------------------+----------------------+
| Study 183              | 77.7%                | 73.9%                |
+------------------------+----------------------+----------------------+
| **No More Than Mild    |                      |                      |
| Heartburn Over 24      |                      |                      |
| Hours^a^**             |                      |                      |
+------------------------+----------------------+----------------------+
| Study 171              | **81.0%^b^**         | 71.6%                |
+------------------------+----------------------+----------------------+
| Study 183              | **81.8%^b^**         | 70.8%                |
+------------------------+----------------------+----------------------+
| ^a^ Percentage of      |                      |                      |
| subjects with          |                      |                      |
| indicated outcome.     |                      |                      |
| Treatment difference   |                      |                      |
| tested using           |                      |                      |
| C                      |                      |                      |
| ochran-Mantel-Haenszel |                      |                      |
| chi-square test with   |                      |                      |
| Investigator as a      |                      |                      |
| stratification         |                      |                      |
| variable.              |                      |                      |
|                        |                      |                      |
| ^b^ Comparisons with   |                      |                      |
| placebo that resulted  |                      |                      |
| in a *p-*values ≤ 0.05 |                      |                      |
| are shaded and bolded  |                      |                      |
| in table.              |                      |                      |
+------------------------+----------------------+----------------------+

Over 14 Dosing Days

Table 6.7 shows the results for the secondary parameters No Nocturnal
Symptoms and Symptoms No More than Mild over 24 hours, across 14
consecutive days of dosing.\
Ome-Mg‑treated subjects had a greater percentage of nights with No
Nocturnal Heartburn symptoms. Consecutive daily dosing with Ome-Mg also
resulted in a greater percentage of days with No More than Mild
heartburn versus placebo. For all outcomes, Ome-Mg 20 provided
significantly greater protection against heartburn than placebo in both
studies.

+-----------------------------------+-----------------+-----------------+
| ##                                |                 |                 |
| # Table 6.7 Mean Percentage of Da |                 |                 |
| ys (Adjusted) with Indicated Outc |                 |                 |
| ome Over 14 Days of Double-Blind  |                 |                 |
| Phase^a^  Heartburn Over a Full D |                 |                 |
| ay Intent-to-Treat Subjects {#tab |                 |                 |
| le-6.7-mean-percentage-of-days-ad |                 |                 |
| justed-with-indicated-outcome-ove |                 |                 |
| r-14-days-of-double-blind-phasea- |                 |                 |
| heartburn-over-a-full-day-intent- |                 |                 |
| to-treat-subjects .Table-heading} |                 |                 |
+-----------------------------------+-----------------+-----------------+
|                                   | Ome-Mg 20       | Placebo         |
+-----------------------------------+-----------------+-----------------+
| No Nocturnal Heartburn^b^         |                 |                 |
+-----------------------------------+-----------------+-----------------+
| Study 171                         | **84.7%^c^**    | 74.5%           |
+-----------------------------------+-----------------+-----------------+
| Study 183                         | **86.1%^c^**    | 75.4%           |
+-----------------------------------+-----------------+-----------------+
| No More Than Mild Heartburn Over  |                 |                 |
| 24 Hours^b^                       |                 |                 |
+-----------------------------------+-----------------+-----------------+
| Study 171                         | **88.6%^c^**    | 75.9%           |
+-----------------------------------+-----------------+-----------------+
| Study 183                         | **88.6%^c^**    | 73.7%           |
+-----------------------------------+-----------------+-----------------+
| ^a^ Percentage based on number of |                 |                 |
| days with valid data. Subjects    |                 |                 |
| with less than 5 days of valid    |                 |                 |
| data were excluded from this      |                 |                 |
| analysis.                         |                 |                 |
|                                   |                 |                 |
| ^b^ Estimated mean percent of     |                 |                 |
| days with indicated outcome       |                 |                 |
| (least squares mean from ANOVA    |                 |                 |
| model with Treatment and          |                 |                 |
| Investigator as factors).         |                 |                 |
| Treatment difference tested using |                 |                 |
| t-test.                           |                 |                 |
|                                   |                 |                 |
| ^c^ Comparisons with placebo that |                 |                 |
| resulted in *p*-values ≤ 0.05 are |                 |                 |
| shaded and bolded in table.       |                 |                 |
+-----------------------------------+-----------------+-----------------+

As seen in Table 6.8, the results for primary and secondary variables
across 14 days are generally corroborated by a GEE analysis of the data
across 14 days of dosing.

+-----------------------+--------------+--------------+--------------+
| ### Table 6.8 Analys  |              |              |              |
| is of Efficacy Variab |              |              |              |
| les Using GEE Treatme |              |              |              |
| nt Comparisons Based  |              |              |              |
| on All 14 days of Dou |              |              |              |
| ble-Blind Phase  Hear |              |              |              |
| tburn Over a Full Day |              |              |              |
|  Intent-to-Treat Subj |              |              |              |
| ects {#table-6.8-anal |              |              |              |
| ysis-of-efficacy-vari |              |              |              |
| ables-using-gee-treat |              |              |              |
| ment-comparisons-base |              |              |              |
| d-on-all-14-days-of-d |              |              |              |
| ouble-blind-phase-hea |              |              |              |
| rtburn-over-a-full-da |              |              |              |
| y-intent-to-treat-sub |              |              |              |
| jects .Table-heading} |              |              |              |
+-----------------------+--------------+--------------+--------------+
|                       | **Ome-Mg [20 |              |              |
|                       | vs.          |              |              |
|                       | Placebo]{.   |              |              |
|                       | smallcaps}** |              |              |
+-----------------------+--------------+--------------+--------------+
|                       | **[Odds\     | **[95%       | **[*p*       |
|                       | Ratio]{.sma  | CI]{.sma     | -Value]{.sma |
|                       | llcaps}^a^** | llcaps}^a^** | llcaps}^b^** |
+-----------------------+--------------+--------------+--------------+
| **No Heartburn Over   |              |              |              |
| 24 Hours**            |              |              |              |
+-----------------------+--------------+--------------+--------------+
| > Study 171           | 2.90         | (2.46, 3.42) | **\<0.001**  |
+-----------------------+--------------+--------------+--------------+
| > Study 183           | 3.61         | (3.06, 4.26) | **\<0.001**  |
+-----------------------+--------------+--------------+--------------+
| **No Nocturnal        |              |              |              |
| Heartburn**           |              |              |              |
+-----------------------+--------------+--------------+--------------+
| > Study 171           | 1.90         | (1.57, 2.30) | **\<0.001**  |
+-----------------------+--------------+--------------+--------------+
| > Study 183           | 1.98         | (1.64, 2.38) | **\<0.001**  |
+-----------------------+--------------+--------------+--------------+
| **No More Than Mild   |              |              |              |
| Heartburn Over 24     |              |              |              |
| Hours**               |              |              |              |
+-----------------------+--------------+--------------+--------------+
| > Study 171           | 2.40         | (1.97, 2.93) | **\<0.001**  |
+-----------------------+--------------+--------------+--------------+
| > Study 183           | 2.67         | (2.20, 3.24) | **\<0.001**  |
+-----------------------+--------------+--------------+--------------+
| a Estimated odds      |              |              |              |
| ratio and 95%         |              |              |              |
| confidence interval   |              |              |              |
| (CI) obtained from    |              |              |              |
| GEE model with        |              |              |              |
| Treatment, Center,    |              |              |              |
| and Day as            |              |              |              |
| categorical           |              |              |              |
| explanatory variables |              |              |              |
| (exchangeable         |              |              |              |
| correlation assumed). |              |              |              |
| Robust variance       |              |              |              |
| estimate used. The    |              |              |              |
| odds ratio is the     |              |              |              |
| ratio of the          |              |              |              |
| estimated odds of     |              |              |              |
| having the indicated  |              |              |              |
| outcome in the first  |              |              |              |
| group relative to the |              |              |              |
| second group shown.   |              |              |              |
|                       |              |              |              |
| b *p*-Values for      |              |              |              |
| treatment comparisons |              |              |              |
| from Wald chi-square  |              |              |              |
| test.                 |              |              |              |
+-----------------------+--------------+--------------+--------------+

### Results with Ome-Mg 10: Primary Efficacy Parameter (Heartburn-Free for 24 Hours): Day 1 and Across All 14 Days, and Dose-Response

Subject demographics were comparable across all treatment groups in both
studies.

In each study, a significantly greater percentage of subjects in the
Ome-Mg 10 treatment groups were Heartburn‑Free than in the placebo group
(*p* ≤ 0.003 for the first dose, *p* ≤ 0.05 across 14 doses).

For Day 1 results, in Study 171, Ome-Mg 20 had a significantly higher
percentage of Heartburn-Free subjects than Ome-Mg 10 (*p *= 0.008),
while in study 183, the two doses produced similar levels of
effectiveness for first dose evaluations.

For results across all 14 days of dosing, in Study 183, Ome-Mg 20 had a
significantly higher percentage of Heartburn-Free subjects than Ome-Mg
10 (p ≤ 0.05), while in study 171, the two doses produced similar levels
of effectiveness.

Table 6.9 details the results for Ome-Mg 20, Ome-Mg 10, and placebo for
the primary efficacy parameter, percent of subjects with no heartburn
for 24 hours, on Day 1 and across all 14 days.

+----------------------------+-------------+-------------+-------------+
| ### Table 6.9 Mean P       |             |             |             |
| ercentage of Days (Adjuste |             |             |             |
| d) with Indicated Outcome  |             |             |             |
| Over 14 Days of Double-Bli |             |             |             |
| nd Phase^a^  Heartburn Ove |             |             |             |
| r a Full Day Intent-to-Tre |             |             |             |
| at Subjects {#table-6.9-me |             |             |             |
| an-percentage-of-days-adju |             |             |             |
| sted-with-indicated-outcom |             |             |             |
| e-over-14-days-of-double-b |             |             |             |
| lind-phasea-heartburn-over |             |             |             |
| -a-full-day-intent-to-trea |             |             |             |
| t-subjects .Table-heading} |             |             |             |
+----------------------------+-------------+-------------+-------------+
|                            | **Ome-Mg    | **Ome-Mg    | **Placebo** |
|                            | 20**        | 10**        |             |
+----------------------------+-------------+-------------+-------------+
| No Heartburn over 24 Hours |             |             |             |
+----------------------------+-------------+-------------+-------------+
| **Day 1**                  |             |             |             |
+----------------------------+-------------+-------------+-------------+
| Study 171                  | **4         | *           | 32.6%       |
|                            | 9.7%^a,b^** | *41.5%^a^** |             |
+----------------------------+-------------+-------------+-------------+
| Study 183                  | *           | *           | 32.1%       |
|                            | *46.8%^a^** | *45.2%^a^** |             |
+----------------------------+-------------+-------------+-------------+
| **Day 14**                 |             |             |             |
+----------------------------+-------------+-------------+-------------+
| Study 171                  | *           | *           | 42.7%       |
|                            | *69.7%^a^** | *71.7%^a^** |             |
+----------------------------+-------------+-------------+-------------+
| Study 183                  | *           | *           | 43.0%       |
|                            | *73.0%^a^** | *66.4%^a^** |             |
+----------------------------+-------------+-------------+-------------+
| **Across 14 Days**         |             |             |             |
+----------------------------+-------------+-------------+-------------+
| Study 171                  | *           | *           | 39.4%       |
|                            | *64.4%^a^** | *60.8%^a^** |             |
+----------------------------+-------------+-------------+-------------+
| Study 183                  | **6         | *           | 37.9%       |
|                            | 7.8%^a,b^** | *61.4%^a^** |             |
+----------------------------+-------------+-------------+-------------+
| ^a^ p-values for           |             |             |             |
| comparisons obtained from  |             |             |             |
| Cochran-Mantel-Haenszel    |             |             |             |
| chi-square test with       |             |             |             |
| investigator as a          |             |             |             |
| stratification variable;   |             |             |             |
| significantly different    |             |             |             |
| from placebo (significant  |             |             |             |
| values bolded)             |             |             |             |
|                            |             |             |             |
| ^b^ p-values for           |             |             |             |
| comparisons obtained from  |             |             |             |
| Cochran-Mantel-Haenszel    |             |             |             |
| chi-square test with       |             |             |             |
| investigator as a          |             |             |             |
| stratification variable,   |             |             |             |
| Ome-Mg 20 significantly    |             |             |             |
| difference from Ome-Mg 10  |             |             |             |
+----------------------------+-------------+-------------+-------------+

Table 6.10 shows the GEE analysis over 14 days of the treatment
comparisons (Ome-Mg 20 vs. placebo and Ome-Mg 10) for the primary and
secondary prevention variables.

+-----------------------+-----+--------+------+-----+--------+------+
| #                     |     |        |      |     |        |      |
| ## Table 6.10 Analysi |     |        |      |     |        |      |
| s of Efficacy Variabl |     |        |      |     |        |      |
| es Using GEE Treatmen |     |        |      |     |        |      |
| t Comparisons Based o |     |        |      |     |        |      |
| n All 14 days of Doub |     |        |      |     |        |      |
| le-Blind Phase  Heart |     |        |      |     |        |      |
| burn Over a Full Day  |     |        |      |     |        |      |
| Intent-to-Treat Subje |     |        |      |     |        |      |
| cts {#table-6.10-anal |     |        |      |     |        |      |
| ysis-of-efficacy-vari |     |        |      |     |        |      |
| ables-using-gee-treat |     |        |      |     |        |      |
| ment-comparisons-base |     |        |      |     |        |      |
| d-on-all-14-days-of-d |     |        |      |     |        |      |
| ouble-blind-phase-hea |     |        |      |     |        |      |
| rtburn-over-a-full-da |     |        |      |     |        |      |
| y-intent-to-treat-sub |     |        |      |     |        |      |
| jects .Table-heading} |     |        |      |     |        |      |
+-----------------------+-----+--------+------+-----+--------+------+
|                       | **  |        |      | **  |        |      |
|                       | Ome |        |      | Ome |        |      |
|                       | -Mg |        |      | -Mg |        |      |
|                       | [20 |        |      | [20 |        |      |
|                       | vs. |        |      | vs. |        |      |
|                       | P   |        |      | O   |        |      |
|                       | lac |        |      | ]{. |        |      |
|                       | ebo |        |      | sma |        |      |
|                       | ]{. |        |      | llc |        |      |
|                       | sma |        |      | aps |        |      |
|                       | llc |        |      | }me |        |      |
|                       | aps |        |      | -Mg |        |      |
|                       | }** |        |      | 1   |        |      |
|                       |     |        |      | 0** |        |      |
+-----------------------+-----+--------+------+-----+--------+------+
|                       | **  | **[95% | **   | **  | **[95% | **   |
|                       | [Od | CI     | [*P* | [Od | CI     | [*P* |
|                       | ds\ | ]{.sma | -Val | ds\ | ]{.sma | -Val |
|                       | Ra  | llcaps | ue]{ | Ra  | llcaps | ue]{ |
|                       | tio | }^a^** | .sma | tio | }^a^** | .sma |
|                       | ]{. |        | llca | ]{. |        | llca |
|                       | sma |        | ps}^ | sma |        | ps}^ |
|                       | llc |        | b^** | llc |        | b^** |
|                       | aps |        |      | aps |        |      |
|                       | }^a |        |      | }^a |        |      |
|                       | ^** |        |      | ^** |        |      |
+-----------------------+-----+--------+------+-----+--------+------+
| **No Heartburn Over   |     |        |      |     |        |      |
| 24 Hours**            |     |        |      |     |        |      |
+-----------------------+-----+--------+------+-----+--------+------+
| > Study 171           | 2   | (2.46, | **\  | 1   | (1.00, | *    |
|                       | .90 | 3.42)  | <0.0 | .18 | 1.40)  | *0.0 |
|                       |     |        | 01** |     |        | 50** |
+-----------------------+-----+--------+------+-----+--------+------+
| > Study 183           | 3   | (3.06, | **\  | 1   | (1.12, | **\  |
|                       | .61 | 4.26)  | <0.0 | .32 | 1.56)  | <0.0 |
|                       |     |        | 01** |     |        | 01** |
+-----------------------+-----+--------+------+-----+--------+------+
| **No Nocturnal        |     |        |      |     |        |      |
| Heartburn**           |     |        |      |     |        |      |
+-----------------------+-----+--------+------+-----+--------+------+
| > Study 171           | 1   | (1.57, | **\  | 1   | (0.92, | 0    |
|                       | .90 | 2.30)  | <0.0 | .12 | 1.38)  | .259 |
|                       |     |        | 01** |     |        |      |
+-----------------------+-----+--------+------+-----+--------+------+
| > Study 183           | 1   | (1.64, | **\  | 1   | (1.06, | *    |
|                       | .98 | 2.38)  | <0.0 | .30 | 1.60)  | *0.0 |
|                       |     |        | 01** |     |        | 11** |
+-----------------------+-----+--------+------+-----+--------+------+
| **No More Than Mild   |     |        |      |     |        |      |
| Heartburn Over 24     |     |        |      |     |        |      |
| Hours**               |     |        |      |     |        |      |
+-----------------------+-----+--------+------+-----+--------+------+
| > Study 171           | 2   | (1.97, | **\  | 1   | (0.99, | 0    |
|                       | .40 | 2.93)  | <0.0 | .23 | 1.51)  | .059 |
|                       |     |        | 01** |     |        |      |
+-----------------------+-----+--------+------+-----+--------+------+
| > Study 183           | 2   | (2.20, | **\  | 1   | (1.01, | *    |
|                       | .67 | 3.24)  | <0.0 | .25 | 1.55)  | *0.0 |
|                       |     |        | 01** |     |        | 42** |
+-----------------------+-----+--------+------+-----+--------+------+
| a Estimated odds      |     |        |      |     |        |      |
| ratio and 95%         |     |        |      |     |        |      |
| confidence interval   |     |        |      |     |        |      |
| (CI) obtained from    |     |        |      |     |        |      |
| GEE model with        |     |        |      |     |        |      |
| Treatment, Center,    |     |        |      |     |        |      |
| and Day as            |     |        |      |     |        |      |
| categorical           |     |        |      |     |        |      |
| explanatory variables |     |        |      |     |        |      |
| (exchangeable         |     |        |      |     |        |      |
| correlation assumed). |     |        |      |     |        |      |
| Robust variance       |     |        |      |     |        |      |
| estimate used. The    |     |        |      |     |        |      |
| odds ratio is the     |     |        |      |     |        |      |
| ratio of the          |     |        |      |     |        |      |
| estimated odds of     |     |        |      |     |        |      |
| having the indicated  |     |        |      |     |        |      |
| outcome in the first  |     |        |      |     |        |      |
| group relative to the |     |        |      |     |        |      |
| second group shown.   |     |        |      |     |        |      |
|                       |     |        |      |     |        |      |
| b *p*-Values for      |     |        |      |     |        |      |
| treatment comparisons |     |        |      |     |        |      |
| from Wald chi-square  |     |        |      |     |        |      |
| test.                 |     |        |      |     |        |      |
+-----------------------+-----+--------+------+-----+--------+------+

Tables 6.11 and 6.12 show the day-by-day results for Ome-Mg 10 vs.
placebo. For study 171, most of the therapeutic gain is realized by Day
7 for Ome-Mg 10, and by Day 6 for Ome-Mg 10 in study 183.

Comparing Tables 6.4/6.5 with Tables 6.11/6.12, it can be seen that
Ome-Mg 20 produced a stronger result earlier than Ome-Mg10, confirming
the known pharmacology of Ome-Mg (see Section 3.0).

+-------+-------+--------------+-------+--------------+-------------+
| #     |       |              |       |              |             |
| ## Ta |       |              |       |              |             |
| ble 6 |       |              |       |              |             |
| .11 N |       |              |       |              |             |
| umber |       |              |       |              |             |
|  and  |       |              |       |              |             |
| Perce |       |              |       |              |             |
| nt of |       |              |       |              |             |
|  Subj |       |              |       |              |             |
| ects  |       |              |       |              |             |
| with  |       |              |       |              |             |
| no he |       |              |       |              |             |
| artbu |       |              |       |              |             |
| rn ov |       |              |       |              |             |
| er 24 |       |              |       |              |             |
|  hour |       |              |       |              |             |
| s, by |       |              |       |              |             |
|  day  |       |              |       |              |             |
|  Stud |       |              |       |              |             |
| y 171 |       |              |       |              |             |
| : Int |       |              |       |              |             |
| ent-t |       |              |       |              |             |
| o-Tre |       |              |       |              |             |
| at Su |       |              |       |              |             |
| bject |       |              |       |              |             |
| s {#t |       |              |       |              |             |
| able- |       |              |       |              |             |
| 6.11- |       |              |       |              |             |
| numbe |       |              |       |              |             |
| r-and |       |              |       |              |             |
| -perc |       |              |       |              |             |
| ent-o |       |              |       |              |             |
| f-sub |       |              |       |              |             |
| jects |       |              |       |              |             |
| -with |       |              |       |              |             |
| -no-h |       |              |       |              |             |
| eartb |       |              |       |              |             |
| urn-o |       |              |       |              |             |
| ver-2 |       |              |       |              |             |
| 4-hou |       |              |       |              |             |
| rs-by |       |              |       |              |             |
| -day- |       |              |       |              |             |
| study |       |              |       |              |             |
| -171- |       |              |       |              |             |
| inten |       |              |       |              |             |
| t-to- |       |              |       |              |             |
| treat |       |              |       |              |             |
| -subj |       |              |       |              |             |
| ects  |       |              |       |              |             |
| .Tabl |       |              |       |              |             |
| e-hea |       |              |       |              |             |
| ding} |       |              |       |              |             |
+-------+-------+--------------+-------+--------------+-------------+
| **[\  | **[O  |              | *     |              | **[\        |
| Day   | me-Mg |              | *[Pla |              | Dif         |
| ]{.sm | 10\   |              | cebo\ |              | ference]{.s |
| allca | N=518 |              | N=518 |              | mallcaps}** |
| ps}** | ]{.sm |              | ]{.sm |              |             |
|       | allca |              | allca |              |             |
|       | ps}** |              | ps}** |              |             |
+-------+-------+--------------+-------+--------------+-------------+
|       | **N   | **%^b^**     | **N   | **%^b^**     | **%**       |
|       | ^a^** |              | ^a^** |              |             |
+-------+-------+--------------+-------+--------------+-------------+
| > 1   | 518   | 41.5         | 517   | 32.7         | 8.8         |
+-------+-------+--------------+-------+--------------+-------------+
| > 2   | 518   | 50.0         | 515   | 35.3         | 14.7        |
+-------+-------+--------------+-------+--------------+-------------+
| > 3   | 516   | 55.8         | 516   | 34.9         | 20.9        |
+-------+-------+--------------+-------+--------------+-------------+
| > 4   | 516   | 55.8         | 515   | 37.7         | 18.1        |
+-------+-------+--------------+-------+--------------+-------------+
| > 5   | 515   | 58.8         | 514   | 35.2         | 23.6        |
+-------+-------+--------------+-------+--------------+-------------+
| > 6   | 516   | 60.3         | 513   | 41.1         | 19.2        |
+-------+-------+--------------+-------+--------------+-------------+
| > 7   | 515   | 62.7         | 514   | 38.1         | 24.6        |
+-------+-------+--------------+-------+--------------+-------------+
| > 8   | 513   | 62.6         | 511   | 36.6         | 26.0        |
+-------+-------+--------------+-------+--------------+-------------+
| > 9   | 512   | 64.1         | 508   | 40.6         | 23.5        |
+-------+-------+--------------+-------+--------------+-------------+
| > 10  | 513   | 63.2         | 510   | 40.4         | 22.8        |
+-------+-------+--------------+-------+--------------+-------------+
| > 11  | 513   | 63.9         | 511   | 41.7         | 22.2        |
+-------+-------+--------------+-------+--------------+-------------+
| > 12  | 513   | 64.5         | 507   | 39.6         | 24.9        |
+-------+-------+--------------+-------+--------------+-------------+
| > 13  | 504   | 70.8         | 497   | 45.5         | 25.3        |
+-------+-------+--------------+-------+--------------+-------------+
| > 14  | 472   | 70.6         | 464   | 47.0         | 23.6        |
+-------+-------+--------------+-------+--------------+-------------+
| ^a^   |       |              |       |              |             |
| N     |       |              |       |              |             |
| umber |       |              |       |              |             |
| of    |       |              |       |              |             |
| ITT   |       |              |       |              |             |
| sub   |       |              |       |              |             |
| jects |       |              |       |              |             |
| in    |       |              |       |              |             |
| trea  |       |              |       |              |             |
| tment |       |              |       |              |             |
| group |       |              |       |              |             |
| with  |       |              |       |              |             |
| n     |       |              |       |              |             |
| on-mi |       |              |       |              |             |
| ssing |       |              |       |              |             |
| v     |       |              |       |              |             |
| alues |       |              |       |              |             |
|       |       |              |       |              |             |
| ^b^   |       |              |       |              |             |
| Pe    |       |              |       |              |             |
| rcent |       |              |       |              |             |
| of    |       |              |       |              |             |
| sub   |       |              |       |              |             |
| jects |       |              |       |              |             |
| with  |       |              |       |              |             |
| No    |       |              |       |              |             |
| Hear  |       |              |       |              |             |
| tburn |       |              |       |              |             |
| over  |       |              |       |              |             |
| 24    |       |              |       |              |             |
| hours |       |              |       |              |             |
+-------+-------+--------------+-------+--------------+-------------+

+-------+-------+--------------+-------+--------------+-------------+
| #     |       |              |       |              |             |
| ## Ta |       |              |       |              |             |
| ble 6 |       |              |       |              |             |
| .12 N |       |              |       |              |             |
| umber |       |              |       |              |             |
|  and  |       |              |       |              |             |
| Perce |       |              |       |              |             |
| nt of |       |              |       |              |             |
|  Subj |       |              |       |              |             |
| ects  |       |              |       |              |             |
| with  |       |              |       |              |             |
| no he |       |              |       |              |             |
| artbu |       |              |       |              |             |
| rn ov |       |              |       |              |             |
| er 24 |       |              |       |              |             |
|  hour |       |              |       |              |             |
| s, by |       |              |       |              |             |
|  day  |       |              |       |              |             |
|  Stud |       |              |       |              |             |
| y 183 |       |              |       |              |             |
| : Int |       |              |       |              |             |
| ent-t |       |              |       |              |             |
| o-Tre |       |              |       |              |             |
| at Su |       |              |       |              |             |
| bject |       |              |       |              |             |
| s {#t |       |              |       |              |             |
| able- |       |              |       |              |             |
| 6.12- |       |              |       |              |             |
| numbe |       |              |       |              |             |
| r-and |       |              |       |              |             |
| -perc |       |              |       |              |             |
| ent-o |       |              |       |              |             |
| f-sub |       |              |       |              |             |
| jects |       |              |       |              |             |
| -with |       |              |       |              |             |
| -no-h |       |              |       |              |             |
| eartb |       |              |       |              |             |
| urn-o |       |              |       |              |             |
| ver-2 |       |              |       |              |             |
| 4-hou |       |              |       |              |             |
| rs-by |       |              |       |              |             |
| -day- |       |              |       |              |             |
| study |       |              |       |              |             |
| -183- |       |              |       |              |             |
| inten |       |              |       |              |             |
| t-to- |       |              |       |              |             |
| treat |       |              |       |              |             |
| -subj |       |              |       |              |             |
| ects  |       |              |       |              |             |
| .Tabl |       |              |       |              |             |
| e-hea |       |              |       |              |             |
| ding} |       |              |       |              |             |
+-------+-------+--------------+-------+--------------+-------------+
| **[\  | **[O  |              | *     |              | **[\        |
| Day   | me-Mg |              | *[Pla |              | Dif         |
| ]{.sm | 10\   |              | cebo\ |              | ference]{.s |
| allca | N=520 |              | N=520 |              | mallcaps}** |
| ps}** | ]{.sm |              | ]{.sm |              |             |
|       | allca |              | allca |              |             |
|       | ps}** |              | ps}** |              |             |
+-------+-------+--------------+-------+--------------+-------------+
|       | **N   | **%^b^**     | **N   | **%^b^**     | **%**       |
|       | ^a^** |              | ^a^** |              |             |
+-------+-------+--------------+-------+--------------+-------------+
| > 1   | 519   | 45.3         | 520   | 32.1         | 13.2        |
+-------+-------+--------------+-------+--------------+-------------+
| > 2   | 518   | 51.2         | 519   | 31.4         | 19.8        |
+-------+-------+--------------+-------+--------------+-------------+
| > 3   | 519   | 56.3         | 518   | 34.6         | 21.7        |
+-------+-------+--------------+-------+--------------+-------------+
| > 4   | 517   | 58.4         | 516   | 34.1         | 24.3        |
+-------+-------+--------------+-------+--------------+-------------+
| > 5   | 518   | 62.7         | 516   | 40.5         | 22.2        |
+-------+-------+--------------+-------+--------------+-------------+
| > 6   | 515   | 66.0         | 514   | 40.3         | 25.7        |
+-------+-------+--------------+-------+--------------+-------------+
| > 7   | 515   | 66.0         | 514   | 40.1         | 25.9        |
+-------+-------+--------------+-------+--------------+-------------+
| > 8   | 517   | 64.6         | 512   | 38.7         | 25.9        |
+-------+-------+--------------+-------+--------------+-------------+
| > 9   | 516   | 66.1         | 514   | 39.3         | 26.8        |
+-------+-------+--------------+-------+--------------+-------------+
| > 10  | 516   | 61.4         | 511   | 37.8         | 23.6        |
+-------+-------+--------------+-------+--------------+-------------+
| > 11  | 515   | 63.5         | 512   | 38.7         | 24.8        |
+-------+-------+--------------+-------+--------------+-------------+
| > 12  | 513   | 64.1         | 509   | 39.1         | 25.0        |
+-------+-------+--------------+-------+--------------+-------------+
| > 13  | 504   | 68.3         | 499   | 42.1         | 26.2        |
+-------+-------+--------------+-------+--------------+-------------+
| > 14  | 486   | 67.3         | 480   | 44.0         | 23.3        |
+-------+-------+--------------+-------+--------------+-------------+
| ^a^   |       |              |       |              |             |
| N     |       |              |       |              |             |
| umber |       |              |       |              |             |
| of    |       |              |       |              |             |
| ITT   |       |              |       |              |             |
| sub   |       |              |       |              |             |
| jects |       |              |       |              |             |
| in    |       |              |       |              |             |
| trea  |       |              |       |              |             |
| tment |       |              |       |              |             |
| group |       |              |       |              |             |
| with  |       |              |       |              |             |
| n     |       |              |       |              |             |
| on-mi |       |              |       |              |             |
| ssing |       |              |       |              |             |
| v     |       |              |       |              |             |
| alues |       |              |       |              |             |
|       |       |              |       |              |             |
| ^b^   |       |              |       |              |             |
| Pe    |       |              |       |              |             |
| rcent |       |              |       |              |             |
| of    |       |              |       |              |             |
| sub   |       |              |       |              |             |
| jects |       |              |       |              |             |
| with  |       |              |       |              |             |
| No    |       |              |       |              |             |
| Hear  |       |              |       |              |             |
| tburn |       |              |       |              |             |
| over  |       |              |       |              |             |
| 24    |       |              |       |              |             |
| hours |       |              |       |              |             |
+-------+-------+--------------+-------+--------------+-------------+

### Outcomes During the Follow-up Phase

Based on estimates shown in Table 6.13, the first episode of heartburn,
any severity and independent of the need to treat the episode, occurred
for more than 50% of the placebo-treated subjects within 1 day. The
first episode of heartburn occurred within 3 days for 75% of
placebo-treated subjects, and within 4--5 days for 75% of Ome-Mg-treated
subjects. In both studies, Occurrence of Heartburn for the Ome-Mg 20 and
placebo groups was comparable beyond Day 5 or 6. Data was collected by
daily diary for 2 weeks following cessation of dosing.

+--------------+--------------+-------------+------------+------------+
| #            |              |             |            |            |
| ## Table 6.1 |              |             |            |            |
| 3 Number of  |              |             |            |            |
| Days to Firs |              |             |            |            |
| t Occurrence |              |             |            |            |
|  of Heartbur |              |             |            |            |
| n During Fol |              |             |            |            |
| low-up Phase |              |             |            |            |
|  (After Two  |              |             |            |            |
| Weeks Daily  |              |             |            |            |
| Dosing) Per- |              |             |            |            |
| Protocol Sub |              |             |            |            |
| jects {#tabl |              |             |            |            |
| e-6.13-numbe |              |             |            |            |
| r-of-days-to |              |             |            |            |
| -first-occur |              |             |            |            |
| rence-of-hea |              |             |            |            |
| rtburn-durin |              |             |            |            |
| g-follow-up- |              |             |            |            |
| phase-after- |              |             |            |            |
| two-weeks-da |              |             |            |            |
| ily-dosing-p |              |             |            |            |
| er-protocol- |              |             |            |            |
| subjects .Ta |              |             |            |            |
| ble-heading} |              |             |            |            |
+--------------+--------------+-------------+------------+------------+
|              | **50^th^     |             | **75^th^   |            |
|              | Per          |             | Perce      |            |
|              | centile^a^** |             | ntile^a^** |            |
+--------------+--------------+-------------+------------+------------+
|              | 171          | 183         | 171        | 183        |
+--------------+--------------+-------------+------------+------------+
| Ome-Mg 20    | 3            | 3           | 5          | 5          |
+--------------+--------------+-------------+------------+------------+
| Placebo      | 1            | 1           | 3          | 3          |
+--------------+--------------+-------------+------------+------------+
| ^a^          |              |             |            |            |
| Estimated    |              |             |            |            |
| using        |              |             |            |            |
| Kaplan-Meier |              |             |            |            |
| method.      |              |             |            |            |
+--------------+--------------+-------------+------------+------------+

## Efficacy Conclusions

These study results provide substantial evidence of statistically
significant and clinically meaningful effectiveness of Ome-Mg 20,
compared to placebo, in the prevention of frequent heartburn for 24
hours when administered in the morning for 14 consecutive days. The
maximum benefit in complete heartburn prevention was manifest in 5--7
days of dosing, well within the 14-day period.

These studies support the following proposed OTC label use indication
for Ome-Mg 20:

+-----------------------------------------------------------------------+
| -   for **prevention** of the symptoms of frequent heartburn for 24   |
|     hours.                                                            |
+-----------------------------------------------------------------------+

# Consumer Understanding and Behavior Program

This section contains a discussion and evaluation of the data that
examine label understanding and consumer usage patterns of Ome-Mg among
adults. Results of these studies were used to aid in the development of
the proposed OTC label.

The following studies were conducted: two Label Comprehension Studies
02255 and 12179 (in which no medication was dispensed), one De-Selection
Study 17859 in consumers with infrequent heartburn (in which no
medication was dispensed) and one Actual Use Study 007 in which
consumers could purchase and use product.

Collectively, these studies demonstrate the ability of the consumer
population to understand the product label, and use Ome-Mg safely and
effectively according to the product label.

## Label Comprehension Study Number 02255

The objective of the label comprehension study was to determine whether
a population of general consumers, including those targeted to various
aspects of the label, understood the self‑selection, use direction, and
warning language on the proposed OTC label for Ome-Mg.

The study was conducted among 684 consumers recruited by mall-intercept,
by telephone, or through advertising. The study population consisted of
the following groups: general population (included subjects with no or
infrequent heartburn), literate subjects with frequent heartburn,
low-literate subjects with frequent heartburn, subjects with heartburn
who were taking one or more medications listed in the drug-drug
interaction statement, and subjects with heartburn who were pregnant or
nursing.

### Methods

The following key communication objectives were evaluated.

-   Product is intended for use by adults 18 years of age or older for
    the prevention of frequent heartburn.

-   Not to use or to ask a health professional before using if subject:

```{=html}
<!-- -->
```
-   Is allergic to Ome

-   Has any of the general warning symptoms under the "Do not use"
    section of the label

-   Is taking one of the medications listed in the drug-drug interaction
    statement

-   Is currently pregnant or nursing a baby

```{=html}
<!-- -->
```
-   Stop use and ask a doctor if:

```{=html}
<!-- -->
```
-   stomach pain continues or worsens

-   heartburn continues or returns after using every day for 14 days

```{=html}
<!-- -->
```
-   Product should be used only once a day (1 tablet in 24 hours) for 14
    days

-   What to do in the case of overdose

The label tested in this comprehension trial is shown on the following
page.

### Prilosec1 Label Comprehension Label -- Study 02255 {#prilosec1-label-comprehension-label-study-02255 .Table-Heading-ABC .unnumbered}

+------------------------------------+---------------------------------+
| Drug Facts                         | ***Drug Facts (continued)***    |
+------------------------------------+---------------------------------+
| ***Active ingredient (in each      | -   heartburn continues or      |
| tablet) Purpose***                 |     returns after using this    |
|                                    |     product every day for 14    |
| Omeprazole magnesium 20.6 mg       |     days                        |
| ..........................Acid     |                                 |
| reducer                            | **If pregnant or                |
|                                    | breast-feeding**, ask a health  |
| (equivalent to 20 mg omeprazole)   | professional before use.        |
+------------------------------------+---------------------------------+
| ***Uses***                         | **Keep out of reach of          |
|                                    | children.** In case of          |
| -   for **prevention** of frequent | overdose, get medical help or   |
|     heartburn                      | contact a Poison Control Center |
|                                    | right away.                     |
+------------------------------------+---------------------------------+
| -   only for those who suffer      | ***Directions***                |
|     heartburn two or more days a\  |                                 |
|     week                           | Adults 18 years of age and      |
|                                    | older:                          |
+------------------------------------+---------------------------------+
| ***Warnings***                     | -   for prevention of frequent  |
|                                    |     heartburn, swallow 1        |
| **Allergy alert** Do not use if    |     tablet\                     |
| you are allergic to omeprazole     |     with a glass of water in    |
|                                    |     the morning                 |
| **Heartburn Warning. Heartburn can |                                 |
| be a sign of a more serious        | -   take every day for 14 days  |
| condition.** Notify your doctor if |                                 |
| you have had heart-\               | -   do not continue beyond 14   |
| burn for 3 months or longer        |     days unless directed by\    |
| without talking to your doctor.    |     your doctor. If your        |
|                                    |     frequent heartburn          |
|                                    |     continues or returns, it    |
|                                    |     could be a sign of a more   |
|                                    |     serious condition.          |
+------------------------------------+---------------------------------+
| **Do not use**                     | -   do not take more than 1     |
|                                    |     tablet a day                |
| -   if you have trouble swallowing |                                 |
|     food, wheezing, a chronic      | -   do not chew or crush the    |
|     cough or hoarseness, have      |     tablets                     |
|     vomited blood, black/tarry     |                                 |
|                                    | Children under 18 years of age: |
|                                    | ask a doctor                    |
+------------------------------------+---------------------------------+
| > stools, chest pain or            | ***Other Information***         |
| > unexplained weight loss. This    |                                 |
| > may be a sign of a more serious  | -   read the directions,        |
| > condition. See your doctor.      |     warnings and package        |
|                                    |     insert\                     |
| -   if you have a sudden increase  |     before use                  |
|     of your heartburn symptoms     |                                 |
|     with nausea and vomiting;      | -   keep the carton and package |
|     chest pain; pain spreading to  |     insert. They contain        |
|     your arms, neck or shoulders;  |     important information.      |
|     sweating; shortness of breath  |                                 |
|     or lightheadedness. See your   | -   store between 20-25°C       |
|     doctor.                        |     (68-77°F )                  |
|                                    |                                 |
| -   with other acid reducers       | -   protect from moisture       |
+------------------------------------+---------------------------------+
| **Ask a doctor or pharmacist       | ***Inactive ingredients***      |
| before use if you are taking**     | glyceryl monostearate,          |
|                                    | hydroxypropyl cellulose,        |
| -   warfarin (blood thinning       | hydroxypropyl methylcellulose,\ |
|     medicine)                      | iron oxide, magnesium stearate, |
|                                    | methacrylic acid\               |
| -   phenytoin (seizure medicine)   | copolymer, microcrystalline     |
|                                    | cellulose, paraffin,            |
| -   diazepam (anxiety medicine)    |                                 |
|                                    | polyethylene glycol 6000,       |
| -   clarithromycin (antibiotic     | polysorbate 80,                 |
|     medicine)                      | polyvinylpyrrolidone, sodium    |
|                                    | stearyl fumarate, starch,       |
| -   itraconazole (prescription     | sucrose, talc, titanium         |
|     antifungal medicine)           | dioxide, triethyl citrate       |
|                                    |                                 |
| -   ketoconazole (prescription     |                                 |
|     antifungal medicine)           |                                 |
+------------------------------------+---------------------------------+
| **Stop use and ask a doctor if**   |                                 |
|                                    |                                 |
| -   stomach pain continues or      |                                 |
|     worsens                        |                                 |
+------------------------------------+---------------------------------+
|                                    | Safety Feature-Do not use if    |
|                                    | tablet blister unit is open or  |
|                                    | broken.                         |
|                                    |                                 |
|                                    | ***Questions or comments?***    |
|                                    | Call toll free                  |
+------------------------------------+---------------------------------+
| **Keep out of reach of children**. | Distributed By Procter &        |
| In case of overdose, get medical   | Gamble, Cincinnati, OH 45202    |
| help or contact a Poison Control   |                                 |
| Center right away.                 |                                 |
+------------------------------------+---------------------------------+

**Design**

This study was conducted in 12 geographically diverse sites across the
U.S. (primarily shopping malls). A total of 684 subjects, 18 years of
age or older, participated in the study. No study medication was
administered.

Potential subjects were screened (including completion of a REALM
test^51^ for literacy) and placed into one or more of the following
groups: subjects with no or infrequent heartburn, literate subjects with
frequent heartburn, low-literate subjects with frequent heartburn,
subjects with heartburn who were taking one or more medications listed
in the drug-drug interaction statement, and subjects with heartburn who
were pregnant or nursing. Subjects within each group were given a
proposed market label for the OTC product. After allowing them to read
the label, subjects were asked questions to determine their
comprehension of the suitability of the medication for their use. In
addition, condition-specific scenarios were also presented.

+------+---------------+-------------------------------+---------------+
| ###  |               |                               |               |
|  Tab |               |                               |               |
| le 7 |               |                               |               |
| .1 L |               |                               |               |
| abel |               |                               |               |
|  Com |               |                               |               |
| preh |               |                               |               |
| ensi |               |                               |               |
| on S |               |                               |               |
| tudy |               |                               |               |
|  Coh |               |                               |               |
| ort  |               |                               |               |
| Info |               |                               |               |
| rmat |               |                               |               |
| ion  |               |                               |               |
| Stud |               |                               |               |
| y 02 |               |                               |               |
| 255  |               |                               |               |
| {#ta |               |                               |               |
| ble- |               |                               |               |
| 7.1- |               |                               |               |
| labe |               |                               |               |
| l-co |               |                               |               |
| mpre |               |                               |               |
| hens |               |                               |               |
| ion- |               |                               |               |
| stud |               |                               |               |
| y-co |               |                               |               |
| hort |               |                               |               |
| -inf |               |                               |               |
| orma |               |                               |               |
| tion |               |                               |               |
| -stu |               |                               |               |
| dy-0 |               |                               |               |
| 2255 |               |                               |               |
|  .Ta |               |                               |               |
| ble- |               |                               |               |
| head |               |                               |               |
| ing} |               |                               |               |
+------+---------------+-------------------------------+---------------+
| Co   | Number\       | Subject Type                  | Recruitment   |
| hort | of Subjects   |                               | Method        |
+------+---------------+-------------------------------+---------------+
| 1    | 229           | Subjects with no or           | Spontaneous   |
|      |               | infrequent heartburn          | intercept in  |
|      |               |                               | m             |
|      |               |                               | alls/shopping |
|      |               |                               | centers or    |
|      |               |                               | prerecruited  |
+------+---------------+-------------------------------+---------------+
| 2    | 155           | Literate subjects with        |               |
|      |               | frequent heartburn            |               |
+------+---------------+-------------------------------+---------------+
| 3    | 162           | Subjects with frequent        |               |
|      |               | heartburn at a 7^th^--8^th^   |               |
|      |               | grade or lower reading level  |               |
+------+---------------+-------------------------------+---------------+
| 4    | 96            | Subjects with heartburn who   | Advertising   |
|      |               | were taking a medication      | or existing   |
|      |               | listed in the drug-drug       | databases     |
|      |               | interaction statement         |               |
+------+---------------+-------------------------------+---------------+
| 5    | 42            | Subjects with heartburn who   | Advertising   |
|      |               | were pregnant/breastfeeding   | or existing   |
|      |               |                               | databases     |
+------+---------------+-------------------------------+---------------+

Each subject was asked a series of direct questions on self-selection of
the product relative to their own personal experience of heartburn and
conditions of appropriate use (e.g., how many tablets should be taken
per day, how many consecutive days should product be taken, what product
is intended for).

In addition, subjects were asked questions on a series of more than 50
scenarios relative to appropriate selection and use of the product:
questions dealt with appropriate use in scenarios of use for prevention
of frequent heartburn to treatment of episodic heartburn, scenarios of
self‑selection, scenarios related to specific warnings (including use
with concomitant medication, use while pregnant/nursing, use with
general warning symptoms present, and general use directions). Study
participants were presented a scenario and then asked a question to
determine if they understood how to use the product.

### Results

All consumers identified Ome-Mg as a product for heartburn. Overall, 76%
to 96% of respondents correctly answered questions about prevention of
frequent heartburn scenarios.

Self-selection results indicated that 99% of the consumers with frequent
heartburn understood that this was a product they could use.
Seventy-eight percent (78%) of the no heartburn/ infrequent heartburn
subjects correctly indicated the product was [not]{.underline} intended
for them.

Scenarios on all label warnings had a high level of correct/acceptable
responses (88% to 100%). The majority of respondents understood they
were to take 1 tablet a day (95%) for 14 days (91%) and that they should
not take the product for more than 14 days (92%).

Half (50%) the subjects taking labeled medications with a potential for
drug-drug interaction indicated they would not use the product or would
consult a doctor prior to use, when such medication was identified on
the label with only the generic drug name. The percent correctly
responding for such medications increased to 82% when brand names of
these medications were also shown. Responses to scenarios on medications
labeled for drug-drug interactions were correct/acceptable 94% to 99% of
the time.

Pregnant/nursing women (91%) knew not to take the product or to ask
their doctor before use. Responses to scenarios relative to pregnancy or
nursing were correct/acceptable 99% of the time.

For consumers with a general condition warning symptom as identified in
the "Do Not Use" section of the label (in other words, a symptom often
confused with heartburn or one which might indicate presence of a more
serious underlying condition, such as chest pain, wheezing, or trouble
swallowing), scores for understanding on direct scenarios were
considerably higher than the direct self-selection question (41%),
indicating consumers understood the warning but may not have felt it
applied to them. Scenarios on general condition warning symptoms showed
a high level of understanding (89% to 100%).

When comparing literate vs. low-literate frequent heartburn subjects,
there were no differences in responses between the groups except for the
following areas: prevention of heartburn use (94% vs. 79%,
respectively); episodic relief of heartburn use (61% vs. 49%,
respectively); label directions (95% to 99% vs. 82% to 89%,
respectively); and label warning direct scenarios "do not use with acid
reducers" and "children under 18 years of age ask a doctor" (89% vs. 97%
and 99% vs. 96% respectively).

### Summary

Overall, consumers with frequent heartburn understood the uses of the
product, the label warnings, and directions in Label Comprehension study
02255. Direct scenarios related to correct product use (prevention of
frequent heartburn) were better understood than direct scenarios related
to incorrect product use (episodic relief). Consumers taking medications
listed in the drug-drug interaction statement understood the warning
better when the brand names were provided. For consumers with a general
condition-warning symptom, scores for understanding on direct scenarios
were considerably higher than the direct self-selection questions,
indicating these subjects understood the warning but may not have felt
it applied to them.

## Label Comprehension Study Number 12179

The inclusion of several elements of information and consumer education
specific to frequent heartburn on the proposed OTC label for Ome-Mg
include general heartburn warning statements, which are indicated as
"general condition warning symptoms". General condition warning symptoms
are included on the label in an attempt to provide the consumer with
additional perspective regarding other conditions which may be confused
with heartburn or may indicate the presence of a more serious underlying
condition, consistent with American College of Gastroenterology (ACG)
guidelines. This language was re-tested in this second Label
Comprehension study to clarify wording, making the warning more
understandable and useful to the consumer.

In the initial Label Comprehension Study 02255, 41% of consumers with
frequent heartburn who had one or more of the general condition warning
symptoms indicated they would not use the product or would ask a doctor
prior to use, even though comprehension scores for the direct scenarios
were much higher (89% to 100%). This indicates that consumers with
general condition warning symptoms understood the label, but, on the
basis of their experience with the condition and/or prior physician
advice, may have felt they did not need to consult a doctor prior to use
of the product if they had already consulted with a physician for the
warning symptom. It is also possible this group did not realize they
needed to be currently experiencing the symptom to report it.

The label warning language for general condition warning symptoms was
modified with consultation from gastroenterologists who participated in
the creation of the original ACG guidelines from which the language
tested in Label Comprehension Study 02255 was derived.^52,64^ The
modified label was retested in Label Comprehension Study 12179 and
results indicate that those consumers who meet label criteria and have
seen a physician for the general condition warning symptom understand
the clarified label language. The label was tested among 145 consumers
who were pre-recruited using market research data collection databases.
The subjects had frequent heartburn and reported one or more of the
general condition warning symptoms relating to the modified label.

The differences in wording for the general condition warning symptoms
warning between the original label tested in Label Comprehension study
02255 and this study is detailed below:

+-----------------------------------+-----------------------------------+
| General Condition Warning         |                                   |
| Symptom: Label Language           |                                   |
+-----------------------------------+-----------------------------------+
| **Label Comprehension Study       | **Label Comprehension Study 12179 |
| 02255**                           | and Proposed Label**              |
+-----------------------------------+-----------------------------------+
| **Do Not Use**                    | **Ask a doctor before use if you  |
|                                   | have**                            |
| -   If you have trouble           |                                   |
|     swallowing food, wheezing, a  | -   Any of the following symptoms |
|     chronic cough or hoarseness,  |     and have not seen a doctor:   |
|     have vomited blood,           |                                   |
|     black/tarry stools, chest     | -- Frequent chest pain            |
|     pain or unexplained weight    |                                   |
|     loss. This may be a sign of a | -- Chest pain; shortness of       |
|     more serious condition. See   | breath; sweating;\                |
|     your doctor.                  | pain spreading to arms, neck or   |
|                                   | shoulders;\                       |
| -   If you have sudden increase   | or lightheadedness                |
|     of your heartburn symptoms    |                                   |
|     with nausea and vomiting;     | -- Trouble swallowing food        |
|     chest pain' chest pain        |                                   |
|     spreading to your arms, neck, | -- Frequent wheezing,             |
|     shoulders; sweating;          | particularly with\                |
|     shortness of breath or        | heartburn                         |
|     lightheadedness. See your     |                                   |
|     doctor.                       | -- Unexplained weight loss        |
|                                   |                                   |
|                                   | These may be signs of a more      |
|                                   | serious condition. Notify your    |
|                                   | doctor.                           |
+-----------------------------------+-----------------------------------+

Results of this research, presented below, indicate consumers with
general condition warning symptoms understand the clarified label.

### Methods

The objective of this study was to evaluate how well the consumer with
frequent heartburn and a general condition warning symptom understood
the conditions (i.e., uses and warnings) under which Ome-Mg could be
used based on reading the label.

Measures of Comprehension

Comprehension was assessed from responses to questionnaires. The
following key communication objectives were evaluated.

-   Product use

-   Consumer self-selection

-   Direct scenarios on the label general condition warning
    contraindicated symptoms

Participants were told to read the label, then asked a series of direct
questions and specific scenarios related to appropriate product use.
Study participants fell into 3 categories: Okay to use (infrequent
general condition warning symptoms); Okay to use (general condition
warning symptoms reported to healthcare provider), and Ask a doctor
first (general condition warning symptoms not yet reported to healthcare
provider).

### Results

Overall, consumers noticed the general condition warning symptoms
warning on the label (97%), and the majority of consumers understood the
general condition warning symptoms on the label. When presented the
direct scenarios relative to the general condition warning symptoms, 92%
to 94% of responses were correct/acceptable. Self-selection among
consumers with frequent heartburn accompanied by a symptom was 81%:
respondents had a correct self-selection response by indicating they
would ask a doctor first, had already talked with their doctor or had
infrequent general condition warning symptoms.

All consumers correctly identified Ome-Mg as a product for heartburn,
and specifically for frequent heartburn by 78% of participants.

### Summary

The understanding and intent of consumers with frequent heartburn and a
general condition warning symptom to comply with this specific aspect of
the label was improved by the modified label language. The wording
included in the final proposed label is a result of this testing
program.

## De-Selection Study Number US0117859 in Consumers With Infrequent Heartburn

In order to understand whether consumers with infrequent heartburn
(symptoms one day per week or less) would understand the intent of the
product label, a study was conducted to assess the de-selection rate for
this population of consumers: the rate at which consumers with
infrequent heartburn did [not]{.underline} choose Ome-Mg as a product
suitable for their heartburn, in the context of the full array of
available OTC heartburn remedies. Although there is no standard method
by which to evaluate de-selection, this research was designed as an
attempt to address the question.

### Methods

The primary objective of this study was to ascertain whether consumers
with infrequent heartburn understood Ome-Mg was not appropriate for
their heartburn when faced with a representative sample of currently
available OTC heartburn medications. The objective was addressed based
on the consumer choosing from a representative variety of OTC heartburn
medications. No subject used the product.

**Design**

Ninety-seven (97) consumers with infrequent heartburn (heartburn once a
week or less) were brought to a simulated retail aisle for OTC heartburn
remedies, complete with products and infrastructure one would expect to
find in a retail grocery, drug, or mass merchandise venue. A
comprehensive array of currently marketed heartburn products was
displayed on the shelf, along with prices. Branded and generic OTC
heartburn products, including Ome-Mg, were on the shelf for
consideration. Ome-Mg was marked with a shelf tag noting it was a new
product, so that consumers would notice it on the shelf, also mimicking
retail presence.

Each consumer first completed a self-administered heartburn habits and
practice questionnaire. The consumer was then taken to the store aisle
where they were instructed to consider their own heartburn needs and
select the heartburn product(s) they would purchase for their own
personal use. They were invited to pick up the products, read labels,
and compare prices just as if they were shopping, and recorded their
selection with the interviewer.

### Results

Ninety-two out of 97 (95%) of consumers with infrequent heartburn chose
another product (not Ome-Mg) as the product most appropriate for their
heartburn. Of the 5 consumers (5%) who did choose Ome-Mg, one cited
experiences of situational frequent heartburn (i.e., daily heartburn
while traveling) as an appropriate use of the product. The majority
(82%) of consumers who decided against using Ome-Mg understood that it
was for frequent heartburn situations.

### Summary

Results from this study indicate it is unlikely that consumers with
infrequent heartburn would select Ome-Mg. When faced with the full array
of currently available OTC products on the shelf plus OTC market-ready
packages of the product, 95% of consumers with infrequent heartburn
selected other OTC heartburn medications more appropriate for their
occasional heartburn.

## Usage Study Number 2001007

Actual Use Study 2001007, (hereinafter referred to as Study 007), was a
three-month study conducted to evaluate the usage patterns and
effectiveness of Ome-Mg in preventing frequent heartburn in a
naturalistic setting. The label tested in the Actual Use trial was the
same as that tested in Label Comprehension study 02255 (section 7.1).

The results of the Actual Use study support the safe use of Ome-Mg 20 by
the OTC consumer with frequent heartburn, and support the ability of the
consumer with frequent heartburn to safely use the product within the
proposed OTC label directions.

### Methods

The primary objective of this study was to investigate how consumers use
Ome-Mg under proposed label conditions in a naturalistic OTC setting. A
secondary objective was to investigate the effectiveness of Ome-Mg in a
naturalistic setting.

The following indicators of consumer behaviors were examined:

-   Percentage of subjects who correctly self-selected to use the study
    medication,

-   Percentage of doses where no more than one tablet of study
    medication was taken per dose,

-   Percentage of dosing days where no more than one dose and no more
    than one tablet of study medication was taken per day, and

-   Percentage of subjects compliant with the 14-day dosing regimen and
    those who took between 11--14 doses of study medication (80% to 100%
    of regimen) in an 11--17 day period (80% to 120% of dosing
    directions).

If a subject took more than 14 doses of the product, they must have
consulted a healthcare provider to be considered compliant with dosing
directions. The study also evaluated physician contact prior to, during,
and immediately after the trial.

Efficacy was assessed from diary entries made by the subjects at Visit
2. Return of heartburn and consumer behavior for treatment of frequent
heartburn after the trial was assessed via follow-up telephone contact
three months after study initiation for that subject.

Design: General Considerations

The three-month study was an open-label, multi-center study and
evaluated use, as needed, of one dose level of Ome-Mg (Ome‑Mg 20) over
an approximate 8-week home-use period. Subjects were recruited via
mall-intercept. Advertising was also used to recruit for this study.
Subjects with a high-school education or less were REALM tested^51^ to
determine reading ability. Subjects determined for themselves whether
the study medication was appropriate for them to use by reading the
proposed package labeling (i.e.*,* subjects self‑ selected whether the
product was appropriate for them to use). Subjects also needed to agree
to purchase product at intended market price to participate, to mimic
consumer decision-making about product use in the market. Information
was collected from subjects on heartburn history, medication and
physician history.

In total, 5060 consumers were approached at the mall and asked, "Do you
get heartburn?" A total of 3061 consumers said no, and 698 consumers
declined to participate in an interview. A total of 1301 consumers were
interviewed as to self-selection, willingness to purchase
medication/participate in a study, and to gather information on
heartburn history (including medication and physician history). A total
of 435 subjects declined to participate further in the trial. Primary
reasons for not participating further included no interest in
participating and the need to check with a healthcare provider before
taking a new medication. In all, 866 subjects indicated they could use
the product and were willing to purchase and use the product. Of those,
758 (89%) subjects used study medication and returned a diary.

Study medication was packaged in 14-count blisters. Subjects were told
at multiple points during the process that they could buy more than one
carton or could return to buy additional product. Subjects were
permitted to buy up to 4 cartons of product during the trial.

The study site was open to each subject for 8 weeks after study
initiation. Subjects could return to the site at any time during that
period to purchase additional product. All kiosks were open during
regular mall hours for the duration of the study.

Return of frequent heartburn, and consumer behavior regarding return of
frequent heartburn after the trial, was assessed via follow-up telephone
contact 4 weeks after the 8-week use period (12 weeks after the initial
interview). Consumers were asked if their frequent heartburn returned
and, if so, what they did.

**Usage Patterns**

Self-selection profiles, usage patterns, and physician utilization
patterns were summarized for the entire study population as well as
specifically for the subgroup with low reading ability and essential
demographics.

**Efficacy Evaluations**

Efficacy of Ome-Mg was assessed at Visit 2 (8 weeks after study
initiation) using a 5-point scale (poor, fair, good, very good,
excellent).

**Statistical Methods**

Descriptive statistics were used to summarize the data. No tests of
hypothesis were undertaken.

**Study Population**

Collectively, 5060 subjects were approached in the mall setting and 1301
agreed to participate in an interview. Of these, 866 identified the
product as one they could use and were willing to purchase the product.
This group constitutes the self-selection population, since they not
only identified that they could use the product but also were willing to
purchase. Twelve subjects were not permitted to purchase product: 4 had
participated in a previous use trial with Ome-Mg, 4 withdrew informed
consent, 3 were \< 18 years of age, and 1 was pregnant. A total of
854 subjects purchased study medication and received a diary, and of
these 758 subjects (89%) used the product and returned a diary from
which usage patterns were determined. The 758 subjects who returned a
diary constitutes the use population.

### Results

#### Demographics of the Self-Selection Population

Demographic data from the population of subjects who returned a diary
(the most complete data set), including the 12 subjects not permitted to
dose (n=770) were discussed in the study report. The population
demographics are shown in Table 7.2.

A more conservative estimate of self-selection, however, is drawn from
the population of subjects who purchased Ome-Mg and received a diary
regardless of whether they returned a diary (n=866), since the
willingness to purchase and use product is an important factor in
self‑selection. This ITT population is comprised of the subjects noted
above as well as the 92 subjects who returned no diary, and 4 subjects
who returned a blank diary.

Of the 866 subjects, 58% were female, 68% were Caucasian, 16% were
Black, and 11% were Hispanic. Subjects averaged 48 years of age (range
18--91) and 8% of subjects had a low reading ability (8^th^ grade or
less) as measured by the REALM test. More than 90% of subjects reported
having heartburn for a year or more, with 90% of these reporting a
history of frequent heartburn (heartburn 2 days per week or more) and
43% reporting heartburn 6--7 days per week. Forty percent (40%) had a
prescription for a heartburn medication within the last year. More than
90% also reported taking an OTC heartburn medication.

Of the 92 subjects who purchased product but did not return a diary, 82
subjects (89%) were lost to follow up, 8 subjects (9%) reconsidered or
withdrew consent, one subject experienced and AE (stomach pains) and
discontinued study medication after 3 doses, and one subject was
withdrawn by the investigator for an AE (burning in the chest,
nausea/vomiting, dizziness, fever, and chills). These 92 subjects
overall tended to have the same duration and history of frequent
heartburn management as those who purchased product and did return a
diary. These subjects also tended to have less frequent heartburn, be
younger, more diverse, and have a slightly higher level of low literacy
than those subjects who returned a diary. Most importantly, of those who
purchased product but did not return a diary, 90 subjects (98%)
purchased only 1 carton of product. Detailed demographic comparisons are
found in Table 7.2.

+-----------------------+-----------------------+-----------------------+
| ### Table 7           |                       |                       |
| .2 Demographic Compar |                       |                       |
| ison Of Subjects who  |                       |                       |
| Purchased Product  an |                       |                       |
| d Returned Diary or D |                       |                       |
| id not Return Diary A |                       |                       |
| ctual Use Study 007 { |                       |                       |
| #table-7.2-demographi |                       |                       |
| c-comparison-of-subje |                       |                       |
| cts-who-purchased-pro |                       |                       |
| duct-and-returned-dia |                       |                       |
| ry-or-did-not-return- |                       |                       |
| diary-actual-use-stud |                       |                       |
| y-007 .Table-heading} |                       |                       |
+-----------------------+-----------------------+-----------------------+
|                       | **Subjects Who        | **Subjects Who        |
|                       | Purchased Product and | Purchased Product and |
|                       | Returned Diary        | Did Not Return Diary  |
|                       | (N=770)^a^**          | (N=92)**              |
+-----------------------+-----------------------+-----------------------+
| Gender (Female)       | 59%                   | 52%                   |
+-----------------------+-----------------------+-----------------------+
| **Race\               | 70%\                  | 50%\                  |
| Caucasian\            | 14%\                  | 33%\                  |
| Black\                | 10%                   | 17%                   |
| Hispanic**            |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Age Mean**          | 49                    | 39.6                  |
+-----------------------+-----------------------+-----------------------+
| **Frequent HB**       | 90%                   | 81%                   |
+-----------------------+-----------------------+-----------------------+
| **Low-Literacy by     | 8%                    | 11%                   |
| REALM**               |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Duration of HB**    | 91% [\>]{.underline}1 | 89% [\>]{.underline}1 |
|                       | year                  | year                  |
+-----------------------+-----------------------+-----------------------+
| Consulted Healthcare  | 48%                   | 54%                   |
| Provider Prior to     |                       |                       |
| Study                 |                       |                       |
+-----------------------+-----------------------+-----------------------+
| History of OTC        | 91%                   | 88%                   |
| Medication Use for HB |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **History of Rx       | 40%                   | 34%                   |
| Medication Use for    |                       |                       |
| HB**                  |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Purchased 1         | 93%                   | 98%                   |
| carton**              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| a Includes 12         |                       |                       |
| subjects who          |                       |                       |
| self-selected to use  |                       |                       |
| Ome-Mg but were not   |                       |                       |
| permitted to          |                       |                       |
| purchase.             |                       |                       |
+-----------------------+-----------------------+-----------------------+

7.4.2.2 Self-Selection Patterns

In order to be counted as having correctly self-selected the product for
use, subjects had to respond correctly to all six self-selection
criteria. Overall, using all six criteria above, 81% correctly
self-selected that Ome-Mg was appropriate for them to use for the ITT
population (n=866). Using only those subjects who returned a diary
(n=758), the correct self-selection rate for all six criteria was 83%.

In the subjects who returned a diary, more than 90% of the subjects had
frequent heartburn on recall (heartburn or heartburn medication use 2
days per week or more). Detailed information on use patterns for
self-selection variables are discussed more fully in section 7.5.3. For
the remaining self-selection criteria:

-   99.9% of those who purchased Ome-Mg were not pregnant or nursing (1
    pregnant)

-   99.6% were age 18 years or older (3 \<18 years of age)

-   100% of the subjects did not have an allergy to Ome.

-   91.7% did not have a general condition warning symptom for which
    they had not already seen a physician (82 with a symptom)

-   98.1% did not take a medication listed in the drug-drug interaction
    section of the label (8 with one of these medications)

7.4.2.3 Consistency with Label Use Directions

Overall, 95% of subjects used only 1 carton (14 tablets or less) of
Ome-Mg during the trial, 2% used 2 cartons, 1% used three cartons, and
1% used 4 cartons.

**One Tablet Per Dose:** Within the study, 96% of subjects took no more
than 1 tablet per dose and 99% of all dosing occasions involved only 1
tablet.

**No More than One Tablet per Day:** Within the study, 91% of all
subjects took no more than 1 dose per day and 98% of all dosing days
involved only 1 tablet.

**11--14 Tablets within 11--17 Days:** Overall, 79% of the subjects
dosed as directed on the label within protocol specifications (11--14
doses within 11--17 days) and/or had consulted with a physician about
heartburn during the trial if they took more than 14 doses. Those who
did not dose exactly according to the label did not dose in a manner
that presents a risk.

**Low-Literacy:** The results noted did not differ appreciably in the
low-reading ability group: 98% took no more than 1 tablet per dosing
occasion, 99% took no more than 1 tablet per dosing day, and 73% dosed
as directed by the label within protocol specifications.

**Other Dosing Patterns:** Dosing patterns different than above
included:

-   those who dosed fewer than 11 tablets (9%)

-   those who dosed 11--14 tablets over fewer than 11 days (\< 1%)

-   those who dosed 11--14 tablets in \> 17 days (9%; of these, 71%
    dosed in more than 30 days)

-   those who dosed more than 14 doses (34 subjects, 5%; 41% of the
    subjects had contacted a healthcare provider during the trial; 85%
    of the subjects had contacted a healthcare provider for frequent
    heartburn before, during, or soon after the trial).

Overall, 53 subjects bought more than one carton of Ome-Mg, and 34
subjects returned a diary for more than 1 carton use. Of the subjects
who purchased more than one carton but didn't return all diaries, a
total of 96 cartons were purchased and 43 diaries were returned.
Assuming worst case usage patterns for this group of subjects, use
patterns would be reported as: 53 subjects may have used more than 1
carton of Ome-Mg (7%) and of these, 15 out of 53 subjects contacted a
doctor during the trial (28%), since no actual use or doctor contact
information is available for those subjects who did not return a diary.

**Efficacy**

An overall assessment of Good, Very Good, or Excellent was reported by
93% of subjects in the study.

Return of Heartburn

A total of 758 subjects returned a diary with product use information,
and 649 subjects (85%) returned information at the 3-month follow-up
telephone call. Of these, 43% did not have frequent heartburn return.

In those in whom frequent heartburn did return, one-third of the
370 subjects whose heartburn returned contacted a doctor and/or took a
prescription medication, and 57% took only an OTC heartburn medication
(65% took an antacid only, 26% took an H~2~RA only, and 9% took both).
An additional 8% of this population did nothing about their returning
heartburn, and the remaining 10% made lifestyle changes.

In the total study population, at the 3 month telephone interview, all
subjects continued to display behavior consistent with label use
directions:

-   43% continued to be free of frequent heartburn symptoms

-   19% contacted a physician and/or took a prescription heartburn
    medication

-   32% took an OTC heartburn medication:

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-   21% took antacids

-   8% took OTC H~2~RAs

-   3% took a combination of antacids and OTC

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```
-   6% did nothing or made a lifestyle modification

Further, of the 373 subjects in whom frequent heartburn did return, only
16 (4%) had taken more than 14 tablets during the trial. Of these 16
subjects, 7 subjects (44%) contacted a doctor during the trial and 15/16
(94%) had consulted a physician about their frequent heartburn either
prior to during or soon after the trial.

Thus, the return of frequent hearburn for 43% of subjects in the Actual
Use study can be measured in months.

**Comparison of Symptom Return Data**

The efficacy trials 171 and 183 utilized a 14-day Ome-Mg 20 course of
therapy in consumers with frequent heartburn. Return of the first
heartburn symptom, of any severity, was evaluated using a daily diary
card for 2 weeks immediately following cessation of therapy, regardless
of whether or not they would have treated that episode. By Day 5 or 6,
the rates of heartburn occurrence per day were similar in those who had
received Ome-Mg 20 and those who had received placebo.

The Actual Use trial was an open label Ome-Mg 20 study in which 90% of
subjects had frequent heartburn and 93% used only a single 14-day course
of therapy. The assessment of return of frequent heartburn during the
Actual Use trial relied on the subject's self‑definition of return of
frequent heartburn, documented by response to a telephone interview
12 weeks after study initiation. The results of the Actual Use trial
demonstrated that, when subjects self-defined "return of frequent
heartburn", 57% had a return of frequent heartburn at the 3-month
telephone interview following a 14-day course of Ome-Mg 20.

In assessing the literature in GERD patients for relapse after 14 days
of Ome 20, results also suggest the time course to return of symptoms is
measured in months. Three studies in the literature evaluated return of
symptoms following a 14- or 28-day course of therapy with Ome 20.

In Carlsson *et al.*^72^, the rate of heartburn recurrence in GERD
patients following cessation of Ome 20 treatment for 4 to 8 weeks was
30% at 1 month following treatment and 75% at 6 months. Relapse was
defined as self-reported by the patient to the investigators and was
defined as recurrent symptoms of any severity on at least 2 days during
the preceding week.

Lind *et al*.^73-74^, reported that the rate of relapse following 4 to 8
weeks of Ome 20 in medically diagnosed GERD patients was less than 5% at
2 months following cessation of dosing. However, these subjects also
used Ome "on demand" for their symptoms, although those who used placebo
in the "on demand" portion of the trial had a relapse rate that exceeded
20% at 2 months. Relapse in these studies was defined as
"discontinuation of treatment due to unwillingness to continue".

In a study by Bardhan *et al.*^62^, GERD patients received 2 weeks of
Ome 20 or an additional 2 weeks of therapy if symptoms had not abated at
the initial treatment. Patients were followed for 1 year for relapse,
defined as moderate to severe symptoms for at least 2 days in each of
the preceding 2 weeks, or the need for 3 doses of antacids per day.
Using this definition, relapse was 72% at 12 months. This study also
noted that successful amelioration of symptoms after 2 weeks of Ome 20
was a powerful prognostic prediction of continued successful control (p
\< 0.0001): 68% of subjects with successful control of symptoms after 2
weeks required no more than three 14-day courses of therapy to control
symptoms over the course of a year. Importantly, 33% of these subjects
required only one 14-day course of Ome 20 for the entire year.
Conversely, those subjects (24% of study) who required an initial course
of therapy beyond 2 weeks tended to require ongoing maintenance
treatment.

The following table details study information for "relapse" from several
published studies, the efficacy studies 171/183, and the Actual Use
study.

+------------+------------+------------+-----------------------------+
| ###        |            |            |                             |
| Table 7.3  |            |            |                             |
| Comparison |            |            |                             |
|  of Relaps |            |            |                             |
| e Endpoint |            |            |                             |
| s in Studi |            |            |                             |
| es with GE |            |            |                             |
| RD Patient |            |            |                             |
| s in the R |            |            |                             |
| x Setting  |            |            |                             |
|  Vs. Studi |            |            |                             |
| es with Fr |            |            |                             |
| equent Hea |            |            |                             |
| rtburn Sub |            |            |                             |
| jects in t |            |            |                             |
| he OTC Eff |            |            |                             |
| icacy and  |            |            |                             |
| Use Studie |            |            |                             |
| s {#table- |            |            |                             |
| 7.3-compar |            |            |                             |
| ison-of-re |            |            |                             |
| lapse-endp |            |            |                             |
| oints-in-s |            |            |                             |
| tudies-wit |            |            |                             |
| h-gerd-pat |            |            |                             |
| ients-in-t |            |            |                             |
| he-rx-sett |            |            |                             |
| ing-vs.-st |            |            |                             |
| udies-with |            |            |                             |
| -frequent- |            |            |                             |
| heartburn- |            |            |                             |
| subjects-i |            |            |                             |
| n-the-otc- |            |            |                             |
| efficacy-a |            |            |                             |
| nd-use-stu |            |            |                             |
| dies .Tabl |            |            |                             |
| e-heading} |            |            |                             |
+------------+------------+------------+-----------------------------+
| **Study**  | **Tr       | **Meas     | **Relapse Endpoints**       |
|            | eatments** | urements** |                             |
+------------+------------+------------+-----------------------------+
| > Ca       | > 4 or 8   | Sel        | [Symptoms]{.underline} of   |
| rlsson^72^ | > weeks    | f-reported | any severity on 2 or more   |
|            |            | to         | days in preceding week      |
|            |            | in         |                             |
|            |            | vestigator |                             |
+------------+------------+------------+-----------------------------+
| > B        | > 2 or 4   | Sel        | [Symptoms]{.underline},     |
| ardhan^62^ | > weeks    | f-reported | moderate to severe for at   |
|            |            | to         | least 2 days in each of     |
|            |            | in         | previous 2 weeks or 3 doses |
|            |            | vestigator | of AA per day               |
+------------+------------+------------+-----------------------------+
| > L        | > 4 or 8   | Sel        | [D                          |
| ind^73-74^ | > weeks    | f-reported | iscontinuation]{.underline} |
|            |            | to         | due to unwillingness to     |
|            |            | in         | continue                    |
|            |            | vestigator |                             |
+------------+------------+------------+-----------------------------+
| > 007      | > 2 weeks  | Sel        | [Symptoms]{.underline}      |
|            |            | f-reported | defined as frequent         |
|            |            | by         | heartburn (per label) by    |
|            |            | telephone  | consumer                    |
|            |            | interview  |                             |
+------------+------------+------------+-----------------------------+
| > 171/183  | > 2 weeks  | Daily      | [First symptom]{.underline} |
|            |            | diary      | of any severity recorded    |
|            |            | cards      | day-by-day                  |
+------------+------------+------------+-----------------------------+

The results in the Actual Use study are closer to that of the published
literature, as are the means of data collection (recall), although
definition of "relapse" differs somewhat from study to study. In
contrast, the results of the efficacy studies, which asked subjects to
record return of any symptom, of any severity, on a prospective
day-by-day basis using a diary, makes not judgment about whether these
subjects would then consider their "frequent heartburn" to have
returned. This is a very different method of data capture and different
definition of return of syptoms. Thus, resuts from the efficacy trials
cannot be compared to the results from the Actual Use trial or published
literature in GERD patients.

**Summary of Self-Selection and General Use Behavior in the Actual Use
Trial 007**

The Actual Use study was designed to look at several endpoints of
consumer behavior relative to the proposed OTC label for Ome-Mg.

The study showed that the label led to highly accurate self-selection.
For each of the 6 self‑selection criteria individually, appropriate
choice was greater than 90% across the population. Over all 6 criteria,
appropriate self-selection was 81% (n=866).

Subjects who elected to use the product were highly compliant with label
dosing instructions. Of the 3 primary compliance parameters for dosing
directions, more than 91% of subjects were consistent with taking no
more than 1 tablet per dose and no more than 1 tablet per day. Overall,
79% of subjects were consistent with the label use directions and/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
frequent heartburn either prior to, during, or soon after the trial.
Only 5 subjects out of 758 took more than 14 doses and did not contact a
doctor.

Overall, 95% of the subjects in the study only used 1 carton (≤ 14
tablets) of study medication.

Further, 93% of subjects rated the product good, very good, or excellent
after the study.

The product label caused consumers to seek increased interaction with
healthcare professionals regarding their heartburn. Overall, 75% of
subjects in the trial had healthcare provider contact about heartburn
prior to, 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 prior to the trial
(48%), and 20% of subjects who had never previously contacted a
physician about frequent heartburn did so during or soon after the trial
for the very first time.

A 14-day regimen of Ome-Mg prevented frequent heartburn from returning
in 43% of subjects at the 3-month follow-up interview. For those in who
frequent heartburn did return, about one‑third saw a physician and/or
took a prescription medication, whereas 57% went to an available OTC
medication (primarily antacids only, indicating that perhaps the
heartburn that returned was less bothersome than had previously been
experienced).

Importantly, this study does not provide evidence for significant
ongoing chronic use, either daily or as needed for symptoms. Even among
those whose frequent heartburn returned, only 16 (4%) used more than 14
tablets, and of those, all but 1 subject had physician contact regarding
heartburn prior to, during or soon after the trial. Therefore, among 649
subjects, only 1 subject took more than 14 tablets, was not in any way
under the care of a healthcare provider for frequent heartburn, and had
frequent heartburn return.

Consumers demonstrated a high level of appropriate self-selection in
meeting all criteria. Consumers also demonstrated a high level of
compliance to the labeled dosing directions in both adherence to the
dosing regimen, and appropriate consultation of the physician.

One SAE was reported in this trial, but was not attributed to Ome-Mg.
Reported AEs were mild and transient, and showed the same general
reporting frequency as in the worldwide post‑marketing surveillance
program for Ome-Mg. The study provides additional assurance that, in an
OTC setting, Ome-Mg is safe for the prevention of frequent heartburn,
and that consumers will be compliant with the proposed OTC labeling.

# Overall Summary of Consumer Behavior (Label Comprehension and Actual Use Studies)

## Ability of the Consumer to Correctly Self-Select the Product for Use

Results of Label Comprehension, De-Selection and Actual Use studies
demonstrate consumers appropriately self-select on the basis of their
frequency of heartburn.

Results of Label Comprehension Study 02255 demonstrate that 99% of
consumers with frequent heartburn knew the product was appropriate for
their heartburn, while 78% of the consumers with no heartburn/infrequent
heartburn indicated correctly the product was not appropriate for their
heartburn based on the product label.

Based on the results of Label Comprehension Study 02255, De-Selection
Study 17859 was specifically designed to better understand behavior of
the consumer with infrequent heartburn. This study was conducted in
consumers with episodic (infrequent) heartburn to assess whether, when
faced with the full array of available OTC heartburn remedies, this
consumer group understood that Ome-Mg was intended to be used by those
with frequent heartburn. Results from this study showed that 95% of
consumers with infrequent heartburn correctly chose a product intended
for occasional heartburn rather than Ome‑Mg.

This was further substantiated by results from the Actual Use study,
which showed that more than 90% of participants who purchased and used
the product were consumers with frequent heartburn. These data from the
label comprehension, de-selection, and actual use studies overall
confirm the ability of consumers to appropriately self-select the
product for use.

## Ability of the Consumer Population to Use the Product as Directed

Label Comprehension and Actual Use studies indicate that consumers
understood and complied with the label directions on how to take the
product: to take one tablet a day, to take the product on 14 consecutive
days, and to seek the advice of a doctor if they needed to take the
product beyond 14 days.

Consumers with frequent heartburn and a low reading ability scored lower
in some aspects in the Label Comprehension study. However, usage
patterns in the Actual Use study were not appreciably different between
the general population and those with a low reading ability for
compliance with label directions, indicating that the label is well
understood.

Results of Label Comprehension Study 02255 demonstrated that consumers
understand the conditions in which they can use the product based on
reading of the carton label. For the use directions, 95% of the subjects
knew to take only 1 tablet per day and 91% knew not to take for more
than 14 consecutive days without consulting a doctor.

In the Actual Use study, 96% of subjects took no more than 1 tablet per
dose (99% of all dosing occasions were one tablet per dose) and 91% of
all subjects took no more than one dose per day (98% of all dosing days
contained only one dose). Overall, 79% of subjects dosed as directed on
the label within protocol specifications and/or had consulted with a
physician about heartburn during the trial.

These results did not differ appreciably in the low-reading ability
group. Ninety-eight percent (98%) took no more than 1 tablet per dosing
occasion, 99% took no more than 1 dose per dosing day and 73% dosed as
directed within protocol specifications.

In the Actual Use study, 93% of the subjects purchased only one carton
of study medication. A total of 53 subjects (7%) bought more than 1
carton of study medication.

Of the subjects who purchased and used study medication, 95% only took 1
carton (≤ 14 tablets) of study medication. Importantly, most subjects
took the product as a regimen; among the few subjects that took the
product intermittently, no subject did so for more than 14 tablets. Only
34 subjects of 758 subjects recorded taking more than 14 doses. Of
these, 41% had contacted a physician during the trial, per label
directions. Thus, the great majority of subjects in this trial did not
exhibit a behavior of long-term dosing without seeking medical advice.

## Ability of the Consumer to Understand the Warnings on the Label

Warning statements for age, allergy, and pregnancy are well understood
by the consumer. Consumer comprehension of drug-drug interactions is
improved by providing brand names, and warning statements for
contraindicated symptoms are improved by clarifying the label warning.

**Age and Allergy:** Label Comprehension Study 02255 indicated that
consumers understood the product is intended for people age 18 years and
older (97%) and that they should not use the product if they are
allergic to Ome (94%). In the Actual Use study, no subjects who were
allergic to Ome self-selected this as a product they could use. Three
subjects (0.4%) less than 18 years of age indicated the product was
appropriate for them to use.

**Pregnancy:** In Label Comprehension Study 02255, 91% of the
pregnant/nursing women (n = 42) knew not to take Ome-Mg or to ask their
doctor before use. In the Actual Use study, one pregnant woman out of
449 women indicated Ome-Mg was a product she could take.

**Drug-Drug Interactions:** In Label Comprehension Study 02255, 50% of
the subjects who were taking a medication listed in the drug-drug
interaction statement indicated they would ask a doctor prior to use.
Correct self‑selection increased to 82% when brand names of these
medications were shown to the subjects. This confirms findings from
previous Label Comprehension studies with Ome‑Mg.

The label used in the Actual Use trial listed 6 medications in the
drug-drug interaction statement: warfarin, phenytoin, diazepam,
clarithromycin, itraconazole and ketoconazole. For reasons described in
the safety section, only 3 of these are included in the proposed OTC
label (warfarin, phenytoin, and ketoconazole).

Overall, 8 subjects (2%) entered the trial taking one of three
medications listed in the proposed OTC label, and of these, 5 subjects
(63%) consulted a physician during the trial about concomitant use.
There were no SAEs reported in this group. Given the high level of
compliance with label directions, the consumer clearly understands the
label warning.

**General Condition Warning Symptoms:** In Label Comprehension Study
02255, 41% of consumers with frequent heartburn and one or more general
condition warning symptoms indicated they would not use the product or
would ask a physician prior to use. Comprehension scores for the direct
scenarios relative to general condition warning symptoms were high (93%
to 99%). These data suggest the consumers understood the warning but
perhaps did not feel the warning language applied to them.

Label Comprehension Study 12179 was conducted to evaluate consumer
understanding of a clarified label for general condition warning
symptoms warnings. The warning language was modified with consultation
from gastroenterologists who proposed the original American College of
Gastroenterology (ACG) guidelines from which the original language was
derived^51^. The new language was intended to be simpler and to clarify
that the warning is intended for those who have not had the symptom
assessed by a physician. Comprehension testing among a specific cohort
of consumers with both frequent heartburn and at least one of the
label-related general condition warning symptoms showed a high level of
understanding of the revised label. Overall, 81% of consumers had a
correct self-selection response. In addition, comprehension of warning
scenarios was 92% to 94%. Results of this research indicate consumers
with general condition warning label symptoms understand the modified
label.

In Actual Use Study 007, 82 subjects of 866 (9%) had a history of
experiencing one or more general warning symptoms without having
previously consulted a doctor about that symptom (70% had already spoken
to a doctor). Seven of the 82 (9%) were previously or currently using
prescription Ome and all took 14 or fewer tablets during the study. None
of these subjects experienced a SAE associated with the condition
defined by these general condition warning symptoms.

Based on the results of Label Comprehension Study 12179, the current
proposed OTC label contains the modified language relative to the
contraindicated symptoms in order to improve consumer comprehension.

## Ability of Consumers to Understand When to Consult a Physician

Label Comprehension and Actual Use studies indicate that consumers
understand when to contact a physician.

Results of Label Comprehension Study 02255 showed that 92% of subjects
knew they should not take the product for more than 14 days unless
directed by their physician.

In the Actual Use study, 48% of the subjects reported having seen a
physician about their frequent heartburn in the prior year. During the
study, 34% (255 subjects) consulted with a physician or had an
appointment to discuss their heartburn. Therefore, in association with
this study, nearly two-thirds as many subjects (34% versus 48%)
consulted with a physician about their frequent heartburn as had done so
in the entire year prior to the study. Importantly 20% of the subjects
who had never consulted a physician for frequent heartburn prior to the
Actual Use study did so during the Actual Use study for the first time.

Of the 34 subjects who took more than 14 doses and returned a diary, 41%
contacted a physician during the study and 85% contacted their doctor
prior to, during, or soon after the study.

For subjects who reported a general warning sign when participating in
the study, 91% had already seen a physician about the condition. For the
82 subjects who entered the Actual Use study and had not previously seen
a physician about their general warning sign, of them (9%) were
previously or currently using prescription Ome. All 82 subjects took 14
or fewer tablets during the study. None of these subjects experienced a
SAE associated with the condition defined by these general condition
warning symptoms, and reported AEs in this group were not different from
those in the general study population.

## Conclusion

In evaluating the complete program of consumer behavior trials, the
label clearly communicates essential elements describing safe and
appropriate use to the consumer seeking an OTC heartburn remedy.
Consumers with infrequent heartburn will not tend to choose Ome-Mg, and
when they do, tend to use the product episodically.

Consumers with frequent heartburn do tend to appropriately choose
Ome-Mg, and comprehension and Actual Use testing demonstrates that they
understand conditions of use, use directions, warning statements on the
label, and when to seek healthcare provider supervision.

# Risk/Benefit of Omeprazole Magnesium in the OTC Setting

This submission establishes that Ome-Mg is safe, effective, and suitable
for prevention of the symptoms of frequent heartburn over 24 hours in an
OTC setting. The pharmacodynamic profile of Ome provides 24-hour control
of gastric acid production, making it an ideal candidate for the
management of frequent heartburn.

Ome-Mg provides a clear and unique benefit to OTC consumers with
frequent heartburn over currently existing therapies. Specifically, for
consumers with heartburn two or more days a week, one 20 mg dose taken
daily provides 24-hour symptom prevention. Statistical and clinically
relevant efficacy is observed on the first day of dosing, on the last
day of dosing, and across 14 days of consecutive daily dosing.

Omeprazole has been widely prescribed, globally, since 1988 for a broad
spectrum of acid‑related disorders. Since its introduction, Ome has been
approved in over 125 countries and over 450 million courses of therapy
have been prescribed. The long history of Ome safety and the
demonstration of effectiveness in the target OTC consumer population
confirm the suitability of OTC Ome at a dose of 20 mg.

Benefits to the OTC Consumer with Frequent Heartburn

The benefit of Ome-Mg 20 in the OTC setting is that the product provides
highly effective prevention of heartburn frequent, as defined by no
heartburn in a 24-hour period. This high level of preventive efficacy
and long duration of action offers a new benefit to the OTC consumer
with frequent heartburn, with the convenience of a single daily dose.

For nocturnal heartburn, first-dose effects were significantly better
than placebo in one of two studies (8.0% for Ome-Mg 20). With
consecutive daily dosing, both studies showed nocturnal heartburn
prevention significantly greater than placebo by 10.2% and 10.7% of the
days for Ome-Mg 20. This result combined with the known pharmacodynamic
profile of Ome, supports the 24-hour duration of effect, since Ome-Mg 20
was dosed in the morning in these two multiple-dose trials.

Thus, the proposed label of 14 days consecutive use of Ome-Mg 20 for
prevention of the symptoms of frequent heartburn for 24 hours fills the
critical gap in OTC heartburn remedies for consumers with frequent
heartburn.

A review of the recent literature confirms that 14 days provides
significant for the amelioration of heartburn. Several 4-week studies in
GERD patients treated with Ome 20 included symptom evaluations at both 2
and 4 weeks. In these studies, 14 days of therapy with Ome 20 was
essentially as effective as 28 days in symptom management. More than 90%
of patients who were heartburn-free at 4 weeks were already
heartburn-free at 2 weeks.^53-63^ These studies, coupled with recent
publications of treatment guidelines for symptomatic reflux have as
their stated objective symptomatic management. Several call for empiric
therapy with acid-reducing agents in the OTC setting, and, if symptoms
can be adequately managed, no further testing or maintenance therapy is
required.^52,64-68^

Potential Risks of Ome-Mg in the OTC Setting

The potential for risks due to Ome-Mg in the OTC setting are very small.
Ome-Mg has been shown to have a bioavailability profile similar to that
of Ome. Safety was evaluated by considering AEs from clinical trials of
both R~x~ Ome and OTC Ome‑Mg indications, as well as worldwide
post-marketing surveillance data for Ome and Ome‑Mg. The sum total of
the safety experience demonstrates Ome-Mg has a wide margin of safety
and an excellent safety profile, especially during long-term use.
Therefore, Ome-Mg is suitable for use and provides a very low risk in
the OTC setting.

Since its introduction in 1988, Ome has been marketed through
prescription in 125 countries. An estimated 450 million courses of
patient therapy have been prescribed worldwide through June 2001, at
daily doses ranging from 10 mg to 360 mg, and at therapeutic durations
of\
4--12 weeks, up to 15 years. Omeprazole's excellent safety profile, as
presented in reviews of worldwide post-marketing surveillance and
clinical trial experience, is established at doses comparable to and
higher than those presented in this submission, and for periods of time
which exceed the proposed OTC duration of use.

A review of R~x~ and OTC clinical trial AE data has not shown any
significant issues or patterns that would prevent Ome-Mg from being used
safely in an OTC setting. Evaluations of the OTC clinical trial AEs show
Ome-Mg has a very similar safety profile as compared to placebo. These
AEs in general are transient and not serious. The most frequently
reported non‑SAEs are diarrhea, headache, nausea, abdominal pain, and
rash.

Gastric acid rebound is not a clinically significant concern with the
short-term use (14 days) of Ome-Mg in the OTC setting.

In addition, there is no evidence there is a causal relationship between
the use of Ome and the development of gastrointestinal cancer in humans.

Ome has an excellent safety profile. There are no additional safety
concerns with unintended use in any population (e.g., children, pregnant
or nursing women). There is minimal potential for drug-drug interaction,
and limited concern about accidental overdose. Finally, there is no
evidence of long-term toxicity, even at much greater exposures.

Safe Use in the OTC Setting (Absence of Physician)

An assessment of the introduction of Ome to the OTC market must include
a careful evaluation of whether it can be safely used by consumers in
the absence of physician involvement.

Omeprazole has a solid safety profile that provides assurance that use
in the OTC setting will not give rise to adverse effects if any
unintended use occurs. Although the drug is intended for use in adults,
the data support safety even if used off-label by children or pregnant
women. There is minimal potential for drug-drug interaction, and the
proposed labeling takes the conservative step to label in cases where
there is any conceivable risk. The data indicate that there is little
risk for harm from accidental or intentional overdose due to the lack of
serious adverse effects even at significant overdoses.

Although the Actual Use study shows high compliance with label
directions, some individuals may continue to have symptoms, ignore the
label directions, and continue to use Ome without physician involvement.
It is the Sponsor's position that such behavior is clearly non-compliant
with the label, and every reasonable step has been taken in product
labeling to discourage it. However, it is necessary to assess the risk
that such behavior might pose to individuals.

The inclusion of the general condition warning symptoms on the label and
observations for the Actual Use trial showed that consumers understand
the wording, and choose, on the basis of their experience with the
symptom and physician consultation, whether or not such wording applies
to them. Of the 82 subjects (out of 866) who entered the use trial with
a general condition warning symptom, none had a SAE associated with the
symptoms defined in the warning language. Reported AEs were mild,
transient, and not different from those reported in the general
population.

The types of non-compliant behavior, which need to be considered, range
from continuous daily use to intermittent use of 14 days therapy.
Literature^62^ indicates that most people who may require more than an
initial 14-day course of therapy will need only 1--3 courses of therapy
to manage symptoms for a year. The study, in GERD patients, showed that
successful amelioration of symptoms after 2 weeks of Ome 20 was a
powerful prognostic prediction of continued successful control
(p \< 0.0001): 68% of subjects with successful control of symptoms after
2 weeks required no more than three 14-day courses of therapy to control
symptoms over the course of a year. Importantly, 33% of these subjects
required only one 14-day course of Ome 20 for the entire year.
Conversely, subjects (24% of the study) who required an initial course
of therapy beyond 2 weeks tended to require ongoing maintenance
treatment. These results are very similar to those found in the Actual
Use trial when return of frequent heartburn was evaluated after a single
14‑day Ome-Mg 20 regimen in the OTC setting. Use of Ome-Mg in this
manner, without physician oversight, is unlikely to present significant
risk.

Any concern is not with those individuals who may have acid-related
disorders, such as erosive esophagitis. If their symptoms are well
controlled, this would be the same therapeutic endpoint that a treating
physician would monitor. Ome-Mg will be a better OTC treatment than
currently available OTC heartburn remedies (without physician
prescription). Relief of frequent heartburn symptoms and healing of
erosive esophagitis, if present, is significantly faster with Ome than
with H~2~RAs. If symptoms are not well controlled with Ome-Mg, each and
every product re-purchase will provide another reminder in the product
labeling that a physician should be consulted.

Concerns about long-term use without physician involvement would be for
individuals who continue to experience symptoms over a long period of
time (\> 12 years).^68,75^

Available data show that the potential for use without physician
involvement is actually limited. Surveys show that up to 75% of
individuals with frequent heartburn have seen their physician regarding
frequent heartburn and that as severity of symptoms change or increases,
so do physician visits.^2,7-8,10,12,16-17,27-34^ In the Actual Use
study, 65% of subjects reported talking to their physician about their
heartburn in the last 5 years. The Actual Use study suggests that the
proposed product labeling results in increased physician contact: in the
3 months of the trial, two-thirds as many subjects saw a healthcare
provider about frequent heartburn as had done so in the prior year (34%
vs. 48%), and 20% of those subjects who had never seen a physician about
frequent heartburn did so for the first time while using the labeled
product. Furthermore, analysis of healthcare provider contact following
the OTC introduction of H~2~RAs shows that such interactions remained
unchanged or increased.^35-38^

Conclusion

The benefits of OTC access to Ome-Mg for the prevention of the symptoms
of frequent heartburn for 24 hours clearly outweigh potential risks. The
pharmacodynamics of the drug, safety and efficacy results of the
clinical program, ability of the consumers to use the product safely
without medical supervision, and low risk of potential negative
consequences coupled with the excellent safety profile of Ome makes this
an excellent product to be used for the prevention of the symptoms of
frequent heartburn in the OTC setting.

The proposed label for Ome-Mg 20 in an OTC setting is congruent with the
supportive data and safety profile.

-   [Target Population]{.underline}: Efficacy and behavioral studies
    were conducted in consumers with frequent heartburn, the target
    population specified on the OTC label. Satisfactory management of
    frequent heartburn is clearly an unmet consumer need, as currently
    available OTC heartburn medications simply do not have the necessary
    pharmacology to meet the demands of frequent heartburn.

-   [Indication]{.underline}: The indication on the proposed label is
    for the prevention of the symptoms of frequent heartburn for 24
    hours. Pharmacokinetic and pharmacodynamic data support the 24‑hour
    duration of action. Efficacy data confirm substantial benefit for
    24‑hour prevention of frequent heartburn after Day 1 and across 14
    days of dosing.

-   [Use Directions]{.underline}: Use directions call for 1 tablet,
    taken every morning for 14 consecutive days. Fourteen days
    consecutive use was the duration tested in the efficacy trials, and
    the proposed label tested in the Actual Use trial showed a high
    level of compliance. Fourteen days Ome 20 therapy has been shown to
    have a clear benefit to the consumer with frequent heartburn, and is
    long enough in the OTC setting.

-   [Healthcare Provider Consultation]{.underline}: If a 14-day course
    of Ome-Mg 20 does not adequately manage frequent heartburn,
    consumers should consult a healthcare professional, as stated in
    several places on the label.

-   [Warnings]{.underline}: The label contains several warning
    statements relative to pregnancy, concomitant medications, and
    general warning signs. Safety data indicates there is no risk should
    unintended use occur in these populations. Label comprehension and
    Actual Use studies show the label language is well comprehended.

In conclusion, Ome-Mg is an excellent and unique OTC candidate to meet
the demands of consumers with frequent heartburn.

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