1 otc omeprazole magnesium (prilosec 1 tm ) october 20, 2000 larry goldkind md division of...
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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”