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OTC Omeprazole Magnesium OTC Omeprazole Magnesium

(Prilosec 1(Prilosec 1TMTM)) October 20, 2000

Larry Goldkind MD Division of Gastrointestinal and

Coagulation Drug ProductsCDER, FDA

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EfficacyEfficacy

• Pharmacodynamics

• Review of Efficacy Trials

• Current Prescription Usage of Prilosec for GERD/Heartburn

• Definitions of GERD: Heartburn

• Current OTC template for Heartburn Medications

• Proposed Prilosec 1 OTC label

• Summary

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Pharmacokinetics and Pharmacokinetics and PharmacodynamicsPharmacodynamics

• Short pharmacokinetic half-life: 0.5-1 hour

• Slow pharmacodynamic onset: Acid inhibition only 50% of maximum at 24 hours

• Long acting pharmacodynamic effect: acid secretion returns to baseline over 3-5 days

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Single-Dose Pharmacodynamic Study: Single-Dose Pharmacodynamic Study: Astra Merck Protocol 129Astra Merck Protocol 129

Intragastric pH vs.. time post-doseIntragastric pH vs.. time post-dose

0

1

2

3

4

5

6

7

15-min

1 Hr 2 Hr 3 Hr 4 Hr 5 Hr

Intr

agas

tric

pH

Omeprazole 10 mg

Omeprazole 20 mg

Famotidine 10 mg

??

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Repeat Dose PharmacodynamicsReference #44

(mean pentagastrin stimulated peak acid output- mmol H/hour

0

5

10

15

20

25

predose 1 dose 4 doses 9 doses

Om-30 mg daily

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Heartburn Relief Trials:

Studies 092 and 095

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Demographics of Studies 092/095

• Mean frequency of heartburn: 60% of days

• Average heartburn severity:

1.8-1.9 (Scale 0-3: moderate=2)

• Over 50 % of subjects had

heartburn severity > 2

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Primary Efficacy Endpoint:Sustained Complete Relief

First Episode/First Dose

0102030405060708090

100

% of Subjects

Study 092N.S.

Study 095N.S.

Placebo Om-10 mg Om-20 mg

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Secondary EndpointsFirst dose

Inconsistent results• Sustained adequate relief

• Complete relief within 1 hour

• Adequate relief within 1 hour

• Overall assessment

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Secondary Analysis“All Episodes Analysis”

• Extent of exposure: almost 90% took more

than 3 doses

• Results beyond first episode are confounded

by pharmacodynamic carry-over effect from

prior doses

• No benefit shown for current OTC

occasional episodic usage

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Sustained Complete Relief “All Episodes” Separated by

at Least 4 days

0102030405060708090

100

% of Subjects

Study092 N.S.

Study095 N.S.

Placebo

Om-10 mgOm-20 mg

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Additional Heartburn Relief Studies

• 3 studies : 017, 018 and 019

• 11,700 subjects enrolled

• No efficacy at study endpoints:

Sustained complete relief Sustained adequate relief Overall assessment of study medication Backup medication

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Summary of Episodic Heartburn Relief

• 5 studies of episodic heartburn relief: Primary analyses all failed

• “All episodes analysis” failed to demonstrate efficacy for occasional episodic usage

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Prevention of Meal-Induced Heartburn

2 studies : 005 ; 006

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Primary Efficacy EndpointHeartburn-Free:4 Hours Post Meal

(% subjects heartburn-free)

Study 005 Study 006

Placebo

Om-10 mg

Om-20 mg

20%

24%(p=0.139)

25%(p=0.057)

17%

25 %(p=0.005)

26%(p=0.004)

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Secondary Endpoints

Supportive Results: 20 mg dose

• Overall assessment of medication• Maximum severity score• Backup medication use• Average symptom severity• Reduction of maximum severity score

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Secondary Endpoints

Supportive Results: 10 mg doseMaximum Severity Score

Not Supportive• Overall assessment • Backup medication use• Average symptom severity• Reduction of maximum severity score

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Conclusions

• Prilosec 1 at 20 mg dose may have marginal efficacy for the prevention of heartburn when taken 1 hour before a heartburn inducing meal

• Prilosec 1 at 10 mg dose lacks replicated efficacy for primary and most meaningful secondary endpoints

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Conclusions (cont.)

Outstanding issues

• Unreplicated results

• Small therapeutic gains compared to placebo

• Consumer confusion due to lack of benefit heartburn relief

• Pharmacodynamics favor chronic use

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24-Hour PreventionStudies 171 and 183

New indication:

24 hour prevention of symptoms for up to 10 days

Is this management of GERD?

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Entry Criteria

• Heartburn of greater than

1 month duration

• Heartburn at least 2 days per week

• Antacid or OTC H2-RA

responsive heartburn in the past (enriched population)

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Demographics

• 80% of subjects:

baseline frequency > 50% of days

• Mean severity 1.5

(2=moderate severity)

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Primary Efficacy EndpointHeartburn-Free Day 1

(% subjects)

Study 171 Study 183

PlaceboOm-10 mgOm-20 mg

33%42%50%

32%45%47%

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Day 14 Heartburn-Free(% subjects)

Study 171 Study 183

PlaceboOm-10 mgOm-20 mg

43%72%70%

43%66%73%

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Summary of Results

• Replicated statistically significant difference compared to placebo

• Efficacy both doses

• Efficacy increases over time Day 1: Therapeutic gain 9-17%

Day 14: Therapeutic gain 23-30%

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Time to Recurrence of Heartburn(% of Subjects Heartburn-Free

Post-Treatment)

0102030405060708090

100

Day 0 Day 1 Day 2 Day 3 Day 4

PlaceboOm-10 mgOm-20 mg

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Conclusions: Daily Dose 24-Hour Prevention Studies

• Successful prevention of heartburn symptoms with 10mg & 20mg doses

• Increased efficacy over time

• Benefit lost within 3 days of discontinuation

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Prescription vs. OTC

GERD vs. Heartburn

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Current Prescription Prilosec Label for GERD

Gastroesophageal Reflux Disease (GERD)

• “The recommended adult oral dose of Prilosec for treatment of patients with symptomatic GERD and no esophageal lesions is 20 mg daily for up to 4 weeks

• The recommended oral dose for the treatment of patients with erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily for 4-8 weeks"

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What Is GERD?Sponsor definition: (page 40 of summary volume) “GERD represents a distinct physician-diagnosed chronic disease characterized by acid reflux and attendant symptoms, usually heartburn …... and requires 4-8 weeks treatment with omeprazole”

“Episodic treatment of heartburn is different from the treatment of GERD.”•Differences not specified

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Definitions of GERD

“GERD may be defined as symptoms and/or tissue injury related to the reflux of gastric contents into the esophagus…….Heartburn is the typical symptom of GERD” (American Society of Gastrointestinal Endoscopy-Guidelines for the Practice of Endoscopy)

“ GERD is used to describe any symptomatic clinical or histopathologic alteration resultant from episodes of gastroesophageal reflux” (Gastrointestinal diseases; Sleisenger and Fortran)

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Definition of GERD (cont.)

Entry criteria from published studies:

“Patients with a history of heartburn for over 12 months and episodes of moderate to severe heartburn on 4 or more of the seven days before endoscopy”

(“Efficacy of omeprazole for the treatment of symptomatic acid reflux disease without esophagitis” Arch Intern Med., June 26, 2000)

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Summary:Heartburn vs. GERD

Heartburn is the cardinal symptom of GERD

GERD– Assessment of GERD requires medical judgement – Management of GERD is based on medical judgement

• Severity• Chronicity• Frequency

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Rationale for OTC Treatment of Episodic Heartburn

• Discrete, episodic, occasional symptoms• Symptoms responsive to low-dose therapy

(1/8 to 1/4 daily prescription dose

of acid suppressive therapies)• OTC product is effective at relief and prevention• No repeat dose carry-over effects required• 2-week limited usage

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Current Template for OTC Acid Suppressive Agents for Heartburn

• For relief of episodic symptoms:

• To prevent symptoms: before eating food or drinking beverages that cause heartburn

• Note: indication linked to a specific episode of heartburn

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Proposed Prilosec 1 OTC label

• For relief of symptoms: No efficacy

• For 24 hour prevention: take anytime during

the day: No data presented

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Proposed Prilosec 1 OTC label(cont.)

• or if you prefer, one hour before those

events associated with occasional

heartburn…….

such as consuming food, beverages: Marginal

efficacy supported

stress, hectic lifestyle, lying down, or exercise:

No supportive data presented

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Proposed Prilosec 1 OTC Label (cont.)

• 24 hour prevention is a new indication for OTC heartburn treatment and is not episodic

• Dose any time of day is an unsupported new dosing instruction and is not episodic

• Non-meal related symptom prevention is an unsupported new indication

• Proposed dose is prescription dose for GERD

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Overall Conclusions

Pharmacodynamic properties predict:

• No efficacy for relief (acute treatment)

• Progressive improvement in efficacy for

prevention over time (delayed PD

effect)

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Overall Conclusions (Cont)

Results of clinical studies follow PD predictions:

• No efficacy at acute treatment of episodic heartburn• Marginal efficacy at 1 hour prevention • Optimal role in prevention of heartburn over time

in the management of GERD, currently “a physician- diagnosed chronic disease requiring 4-8 weeks of therapy”