# Presentation: 286987

##  Clinical Overview Omeprazole Magnesium(Prilosec 1 TM) June 21, 2002

- Mark Avigan, MD CM
- Division of Gastrointestinal and Coagulation
- Drug Products
- CDER, FDA

## Initial Proposed Indications for OTC Omeprazole Mg 

- The relief of heartburn, acid indigestion and sour stomach
- The prevention of heartburn, acid indigestion and sour stomach brought on by consuming food and beverages or other inciting events
- The prevention of symptoms for 24 hours

**(Joint Advisory Committee Oct 20, 2000)**

## Conclusions of First Advisory Committee

- Treatment of episodic heartburn as a symptom** **
- Studies 092 and 095 were negative
- 4 hour prevention of meal-induced heartburn** **
- Studies 005 and 006 did not consistently demonstrate efficacy
- The prevention of symptoms for 24 hours
- Studies 171 and 183 both demonstrated efficacy

## Pharmacological Characteristics of Omeprazole-Mg

- Half-life: 1-2 hours
- Irreversibly binds gastric H+K+ ATPase
- Dosing interval: 24 hours
- Minimal acid suppression after  single dose
- Buildup of PD response over a few days
*   *

*	****The increase**** ****of acid suppression over consecutive daily doses may reinforce continuous unsupervised usage by consumers seeking optimal relief of chronic heartburn***

## Overview of Presentation

- Safety Profile of Omeprazole
- Potential for Long-term OTC Usage
- Results of Pivotal Studies 171 and 183
- Symptoms and Usage in Actual Use Study 007
- Issues to Resolve

## Omeprazole-Mg Safety Profile Toxicity of Short-Term Exposure

- hypersensitivity reactions
- toxic epidermal necrolysis
- agranulocytosis
- liver injury

## Drug-Drug Interactions

- Inhibition of CYP 2C19
- warfarin, phenytoin, diazepam, digoxin
- Gastric acid neutralization
- ketoconazole

## Safety Issues of Long-term OTC  Exposure

- Masking and/or delay in dx of GERD complications and malignancy
- Tumorigenic potential of drug-induced hypergastrinemia and drug-related genotoxicity

## Potential for Long-term OTC Usage

- Effective in heartburn *prevention* but not *treatment of episodes*
- Heartburn recurrence rate is high
- Actual Use studies demonstrate continued unsupervised treatment exceeding labeled instructions

## Currently Proposed Indications

- Prevention of symptoms of frequent heartburn for 24 hrs
- Only for those who suffer heartburn two or more days a week

## Efficacy Studies

- Studies 171 and 183 - double blind placebo controlled 2 week treatment studies; n=500 subjects/treatment arm
- Inclusion criteria - presence of heartburn on at least 2 days/week
- Primary efficacy variable - No heartburn over 24 hours between the 1st and 2nd daily dose

## Study Results

- Subjects with no heartburn:        _Day 1_       _Day 14_
- Placebo      	                                  32% 	43%
- Ome-Mg (20 mg)                          48%        	72%
- Therapeutic gain of Ome-Mg 20 mg vs placebo only 16% on Day 1
- Therapeutic gain increased to 29% on Day 14
- After 14 days of treatment almost 30% of subjects experienced breakthrough heartburn

## Influence of Baseline Heartburn Frequency on Responses

**Heartburn frequency**_**	**_**    Therapeutic Gain**
- 						         (Drug - Placebo)
-           					 % Patients with No Heartburn
- 		 _**% of Days**_** ****	**_**	**_**         **_**Day 1**_**      **_**Day 14**_
**	****	****     ****<50%           ****	****	****            4 %            11%**
**	****	****      ****100% ****	****	****	****          18%****	****          39%**

## Conclusions

- Subjects with Low Frequency Heartburn
- Therapeutic gain was small because of high placebo response rate
- Subjects with Daily Heartburn
- Therapeutic gain was higher because of low placebo response rate
- Breakthrough heartburn was 40% after 14 days of treatment

## GERD*

*Chronic* symptoms (e.g. heartburn) or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus
- Many patients with GERD require *long-term*, *possibly life-long*, therapy
- *Updated Guidelines for the Diagnosis and Treatment of GERD; Am. J. Gastro., 1999

## Characterization of Study Patients

- High degree of overlap with dx of GERD
- After treatment in both studies the recurrence of heartburn was rapid
- Within 3 days after treatment stopped
- the therapeutic gain disappeared
- the daily percentage of subjects with heartburn over 24 hours rose to 55%

## Actual Use Study

- >90% experienced heartburn for >1 yr and
- 50% for > 5 yrs
- 57% experienced heartburn 4 or more days/wk
- Many subjects used other products or prescription medications to relieve recurrent heartburn
- Studies have not measured the potential for long-term intermittent usage

## Cautions Listed in Proposed Labeling

- ‘notify your doctor if you have had heartburn for 3 months or longer without talking to your doctor’
- ‘stop use and ask a doctor if heartburn continues or returns after using this product everyday for 14 days’
- ‘do not continue beyond 14 days unless directed by a doctor’

## Issues to Resolve

- Does a single 14 day treatment course meet the short and long-term needs of consumers?
- Is unsupervised chronic intermittent usage consistent with the sponsor's proposal?
- Is restriction to a single 14 day treatment course an important safety feature?