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

List of Figures. 6

List of Study Numbers and Abbreviations. 9

Briefing Document Organization. 10

1.      Overview of the Briefing Document 11

1.1       Introduction. 11

1.2       Executive Summary. 14

1.2.1       Target Population:  The Consumer Population with Frequent Heartburn. 14

1.2.2       Pharmacology of Omeprazole. 14

1.2.3       Safety. 14

1.2.4       Efficacy. 16

1.2.5       Proposed Dose and Duration for OTC Status. 16

1.2.6       Consumer Label Understanding and Actual Product Use. 18

1.2.7       Risk and Benefit of Ome-Mg in the OTC Setting. 19

1.2.8       The Proposed OTC Label for Ome-Mg. 20

2.      Characterization of the Consumer With Frequent Heartburn. 22

2.1       The Frequent Heartburn Population. 22

2.2       Medication Habits and Practices of the Frequent Heartburn Population. 24

2.3       Medical Utilization Patterns of the Frequent Heartburn Population. 25

2.4       Continuing Health Care Utilization Patterns. 25

2.5       Professional Recommending Patterns. 26

2.6       Heartburn Treatment Guidelines. 26

2.7       Overall Summary. 26

3.      Clinical Pharmacology of Omeprazole. 28

3.1       Inhibition of Gastric Acid Secretion. 29

4.      Summary of Safety. 34

4.1       Brief Summary of Safety Information Submitted in the Original NDA 21-229. 34

4.1.1       Clinical Trials from the OTC Development Program with Omeprazole Magnesium Multiple Unit Pellet System (MUPS) Tablets. 34

4.1.2       Clinical Trials from Prescription Omeprazole Capsules. 35

4.1.3       Prescription Omeprazole Post‑Marketing Surveillance Data. 36

4.2       Safety Update Report 36

4.2.1       Clinical Trial Data. 36

4.2.2       Post-Marketing Data– Ome-Mg (MUPS) Tablet Formulation - SUR.. 37

4.3       Updated Safety Information Included in the Resubmission of NDA 21-229. 37

4.3.1       Clinical Trial Adverse Event Data from P&G Actual Use Study 2001007. 38

4.3.2       Updated Post-Marketing Data – Omeprazole magnesium (MUPS) Tablet Formulation  38

4.4       Other Safety Related Issues. 39

4.4.1       Drug/Drug Interactions. 39

4.4.2       Unintended Use in Special Populations. 39

4.4.2.1       Pregnancy. 39

4.4.2.2       Pediatric/Adolescents. 40

4.5       Overall Safety Conclusion. 41

5.      Clinical Program Overview.. 42

6.      Efficacy Program.. 43

6.1       Study Design and Clinical Methods. 43

6.1.1       Statistical Methods. 44

6.1.2       Demographics and Other Baseline Characteristics. 44

6.2       Efficacy Results. 45

6.2.1       Primary Efficacy Parameter (Heartburn-Free for 24 Hours) 45

6.2.2       Secondary Parameters. 52

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

6.2.4       Outcomes During the Follow-up Phase. 59

6.3       Efficacy Conclusions. 59

7.      Consumer Understanding and Behavior Program.. 60

7.1       Label Comprehension Study Number 02255. 60

7.1.1       Methods. 60

7.1.2       Results. 63

7.1.3       Summary. 63

7.2       Label Comprehension Study Number 12179. 64

7.2.1       Methods. 65

7.2.2       Results. 66

7.2.3       Summary. 66

7.3       De-Selection Study Number US0117859 in Consumers With Infrequent Heartburn  67

7.3.1       Methods. 67

7.3.2       Results. 67

7.3.3       Summary. 67

7.4       Usage Study Number 2001007. 68

7.4.1       Methods. 68

7.4.2       Results. 70

7.4.2.1       Demographics of the Self-Selection Population. 70

8.      Overall Summary of Consumer Behavior (Label Comprehension and Actual Use Studies) 78

8.1       Ability of the Consumer to Correctly Self-Select the Product for Use. 78

8.2       Ability of the Consumer Population to Use the Product as Directed. 78

8.3       Ability of the Consumer to Understand the Warnings on the Label 79

8.4       Ability of Consumers to Understand When to Consult a Physician. 80

8.5       Conclusion. 81

9.      Risk/Benefit of Omeprazole Magnesium in the OTC Setting. 82

10.    References. 86


List of Tables

Page

 

Table 3.1     Ratios of Geometric Means and 95% Confidence Intervals for AUC0 Subjects with Complete Pharmacokinetic Data.. 29

Table 6.1     Demographic and Other Baseline Characteristics  (Studies 171 and 183) 45

Table 6.3     Analysis of Primary Efficacy Variable No Heartburn over 24 Hours on Day 1  Intent-to-Treat Subjects. 47

Table 6.4     Number and Percent of Subjects with no heartburn  over 24 hours, by day  Study 171: Intent-to-Treat Subjects. 49

Table 6.5     Number and Percent of Subjects with no heartburn  over 24 hours, by day  Study 183: Intent-to-Treat Subjects. 50

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  6.7    Mean Percentage of Days (Adjusted) with Indicated Outcome  Over 14 Days of Double-Blind Phasea    Heartburn Over a Full Day  Intent-to-Treat Subjects. 53

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  6.9    Mean Percentage of Days (Adjusted) with Indicated Outcome  Over 14 Days of Double-Blind Phasea    Heartburn Over a Full Day  Intent-to-Treat Subjects. 55

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 6.11   Number and Percent of Subjects with no heartburn  over 24 hours, by day  Study 171: Intent-to-Treat Subjects. 57

Table 6.12   Number and Percent of Subjects with no heartburn  over 24 hours, by day  Study 183: Intent-to-Treat Subjects. 58

Table 6.13   Number of Days to First Occurrence of Heartburn During Follow-up Phase (After Two Weeks Daily Dosing) Per-Protocol Subjects. 59

Table 7.1     Label Comprehension Study Cohort Information Study 02255. 62

Table 7.2     Demographic Comparison Of Subjects who Purchased Product   and Returned Diary or Did not Return Diary Actual Use Study 007. 71

List of Tables (Continued)

Page

 

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

 


List of Figures

Page

Figure 2.1      Frequency of Heartburn in the United States Heartburn Population (1997)3 23

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

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

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

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

Figure 3.4    The Inhibitory Effects of 1 Week of Treatment with  Different Daily Doses of Ome on the 24-Hour Intragastric Acidity71 32

Figure 3.5    Dose Response Curve for Repeated Once Daily Doses of Omeprazole  33

Figure 6.1    Study Schematic for 14-Day Heartburn Prevention Trials. 43

Figure 6.2    Percent of Subjects with 24 Hour Prevention of Heartburn — Day 1  46

Figure 6.3    Percent of Subjects with 24 Hour Prevention of Heartburn — Time Course Over 14 Days Studies 171 and 183. 48

Figure 6.4    Percent of Days with No Heartburn — Across 14 Day Dosing Period   51


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

H2RA(s)

 

Histamine H2-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

Rx

 

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

t½

 

Elimination Half-Life

U.S. or US

 

United States

vs.

 

Versus


List of Study Numbers and Abbreviations

Abbreviation

 

Study Number

007

 

2001007

171

 

AMI 171

183

 

AMI 183

02255

 

02255

12179

 

12179


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 (Rx) 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.

1.Overview of the Briefing Document

 1.1        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 (Rx) 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 tablet)              Purpose

Omeprazole magnesium 20.6 mg …………….……….Acid reducer

(equivalent to 20 mg omeprazole)

If pregnant or breast-feeding, ask a health professional before use. 

 


Keep out of reach of children.  In case of overdose, get medical help or contact a Poison Control Center right away.

Uses

n   for prevention of the symptoms of frequent heartburn for
24 hours

n   only for those who suffer heartburn two or more days a week

Directions

Adults 18 years of age and older:

n   for prevention of frequent heartburn, swallow 1 tablet
with a glass of water in the morning 

Warnings

Allergy alert  Do not use if you are allergic to omeprazole

Heartburn Warning. Heartburn can be a sign of a more serious condition.  Notify your doctor if you have had heart-
burn for 3 months or longer without talking to your doctor.

n   take every day for 14 days

n   do not continue beyond 14 days unless directed by
your doctor.  If your frequent heartburn continues or returns, it could be a sign of a more serious condition. 

n   do not take more than 1 tablet a day

n   do not chew or crush the tablets

Do not use

n   with other acid reducers

Children under 18 years of age: ask a doctor

Ask a doctor before use if you have

n   any of the following symptoms and have not seen a doctor

n   frequent chest pain

n   chest pain with shortness of breath; sweating; pain spreading to arms, neck or shoulders; or lightheadedness

n   trouble swallowing food

n   frequent wheezing, particularly with heartburn

n   unexplained weight loss

These may be signs of more serious conditions. Notify your doctor.

Other Information

n   read the directions, warnings, and package insert before use

n   keep the carton and package insert.  They contain important information.

n   store at 25°C (77°F ); excursions permitted to 15-30°C (59-86°F)

n   avoid product exposure to excessive heat and humidity

n   protect from moisture

Ask a doctor or pharmacist before use if you are taking

n   warfarin (blood thinning medicine)

n   phenytoin (seizure medicine)

n   ketoconazole (prescription antifungal medicine)

Inactive ingredients glyceryl monostearate, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
iron oxide, magnesium stearate, methacrylic acid
copolymer, microcrystalline cellulose, paraffin,

Stop use and ask a doctor if

n   stomach pain continues or worsens

n  heartburn continues or returns after using this product

polyethylene glycol 6000, polysorbate 80, polyvinylpyrrolidone, sodium stearyl fumarate, starch, sucrose, talc, titanium dioxide, triethyl citrate

every day for 14 days

Questions or comments?  Call toll free

Safety Feature-Do not use if tablet blister unit is open or broken.

Distributed By Procter & Gamble, Cincinnati, OH  45202

 

 

 



 

 

 


 1.2        Executive Summary

 

1.2.1         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 population1-2, 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.

 

1.2.2         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. 

 

1.2.3         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 Rx 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 Rx 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 Rx 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 Rx 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 Rx setting exposed to high doses for prolonged periods of time.  Its excellent safety record makes it well suited for OTC status.

 

1.2.4         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.

 

1.2.5         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 Rx 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 Rx 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 study62 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 duration52,66-68 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 Rx 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.

 

1.2.6         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.

 

1.2.7         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.

 

1.2.8         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 H2RAs 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.

 

 

 

 

 

 

2.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 H2-receptor antagonists (H2RAs) 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 consumers1-2, 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. 

 

 2.1        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 years1-3,6-8,10,12,16, and heartburn does have a slight tendency to increase with age.  According to a United States (U.S.) survey conducted in 1995 by Nielsen5, 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

 

Figure 2.1   
Frequency of Heartburn in the United States Heartburn Population (1997)3

 

 

 

Duration: Overall, consumers with frequent 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 

 


 2.2        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 H2RAs to achieve control of frequent heartburn, especially for 24 hours. 

 

How Consumers Manage Frequent Heartburn12

·        80% use antacids

·        48% use OTC H2RAs

  26% use OTC H2RAs ³ 4 days per week

·        47% medicate ³ 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.

 

Figure 2.2  
Volume of OTC Heartburn Product Use by Frequency of Heartburn
(All OTC Users Past 12 months)

 

 

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