OTC Omeprazole Magnesium Prilosec 1TM

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OTC Omeprazole Magnesium (Prilosec 1TM)

• October 20, 2000

Larry Goldkind MD Division of Gastrointestinal
and Coagulation Drug Products CDER, FDA
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Efficacy

• 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 Pharmacodynamics

• 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 Astra Merck
Protocol 129Intragastric pH vs.. time post-dose
??
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Repeat Dose PharmacodynamicsReference 44(mean
pentagastrin stimulated peak acid output- mmol
H/hour
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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 moderate2)
• Over 50 of subjects had
• heartburn severity gt 2

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Primary Efficacy EndpointSustained Complete
Relief First Episode/First Dose
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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 AnalysisAll 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
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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-Free4 Hours
Post Meal( subjects heartburn-free)
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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 dose
• Maximum 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 gt 50 of days
• Mean severity 1.5
• (2moderate severity)

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Primary Efficacy EndpointHeartburn-Free Day 1
( subjects)
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Day 14 Heartburn-Free( subjects)
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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)
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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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SummaryHeartburn 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