# Presentation: 368330

## Clinical Safety ProfileOTC Omeprazole Magnesium (Prilosec 1TM)  

**October 20, 2000**

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

**Notes:**
Introduction
Good Morning,

My name is Mark Avigan

I am a Medical Officer in the Division of Gastrointestinal and Coagulation Drug Products at CDER

## Safety Profile Issues

**Proposed Label - No warning on long-term intermittent use **
**Actual Use Studies - Over 10 days use **
**Maximal Acid Suppression - After 2-3 days of daily 20 mg doses **
**Many subjects had GERD. **

**Notes:**
Safety Profile Issues
As you just heard a number of characteristics of omeprazole and the proposed OTC indication point to  a strong likelihood of chronic or intermittent long-term use by some consumers.  These include:

The Proposed labeling does not warn against long-term intermittent use

Actual Use studies that have been performed by the sponsor indicate that a significant percentage of subjects did not follow label instructions by treating themselves continuously beyond 10 days

Maximal acid suppression only occurs after 2-3 days of daily 20 mg doses.  Also the effects last 3-5 days. These properties are consistent with a role for the prevention of chronic heartburn rather than the immediate relief by a single tablet of occasional episodes of heartburn

A significant percentage of subjects recruited into the OTC studies had GERD.  Heartburn associated with GERD is characterized by a high recurrence rate when treatment is stopped.

Therefore, we need to take into account the safety profile of long-term drug exposure in conjunction with short term exposure as expressed in the labeling that the sponsor has proposed.

## Outline of Talk

**Safety in OTC Omeprazole-Mg Trials**
**Safety of Short-term Omeprazole-Enteric Coated**
**	****	****Clinical Studies, SafeTNet and Literature**
**	****	****Liver, Skin, Bone Marrow, Immune System **
**Post-marketing Safety of Omeprazole-Mg**** **
**Drug-Drug Interactions**
**	**

**Notes:**
Outline of Talk
To pursue this end, the following topics will be discussed
First, the Safety Profile of Omeprazole-Mg in OTC Trials as presented in the NDA
Second, safety issues raised by the experience from the Short-term administration of Enteric coated Omeprazole (12 weeks and less of drug exposure) in which a summary of clinical Studies, the postmarketing data base-SafeTNet and relevant Literature will be summarized.
Special topics of concern that will be addressed today include omeprazole induced toxicity of Liver, skin, Bone Marrow, and the immune system; 
Third, the Post-marketing safety profile of the Magnesium formulation of Omeprazole will be discussed.  Since 1998 this formulation has been prescribed by physicians in Sweden.
Special issues that will be discussed include The potential for Drug-drug interactions between omeprazole  and other drugs

## Outline of Talk (Cont.)

**Special Populations: Adolescents, Pregnant Women**
**Safety Profile of Long-term (more than 12 weeks)**
**	****Masking of Disease**
**	****Tumorigenicity**
**	****Gastric Acid Rebound**
**Conclusions**

**Notes:**
Outline of Talk (Cont.)

In addition, attention will be given to experience to date with omeprazole in two Special Populations: Adolescents and Pregnant women
The second part of this presentation will be an analysis of special concerns that have been raised about Long-term continuous or intermittent administration of Enteric Coated Omeprazole . We have somewhat arbitrarily defined this to mean continuous of intermittent exposure to the drug for more than 12 weeks and in some cases longer than 1 year.  The special topics that will be covered include Masking of medically significant underlying Diseases, Tumorigenicity and the implications of Gastric Acid Rebound upon cessation of drug administration.
Finally, a summary of the Conclusions that we have drawn surrounding these issues will be given.

## Adverse Events - Short-term Exposure4 Databases

***OTC Clinical Trials*****                                                n=8179;  daily 10 mg-20 mg doses;   1-14 days**
***Rx Clinical Trials*****                                                   n=5757; 10 mg-40 mg doses; 1 day-12 weeks**
***Post Marketing Surveillance Databases*****                          SafeTNet; 15,385 AEs (until 6/30/98)              Ome-Mg; 219 AEs (2/98 -12/99)**

**Notes:**
Adverse Events-short term exposure- 4 databases
To begin with, I will discuss the short-term omeprazole exposure safety profile surrounding the different formulations.  There are four databases that are relevant for this analysis.          First, the OTC Ome-Mg clinical trials that formed the body of this NDA application.   These 8179 subjects were exposed to daily 10 mg or 20 mg doses of Ome-Mg - 5,040 study subjects were exposed to 20 mg doses and 3,039 were exposed to 10 mg doses. In most subjects, the duration of treatment ranged between 1 and 14 days and the time frame during adverse events were scored was relatively short.         A second database relevant to short-term omeprazole exposure is that derived from Clinical trials of the Prescription formulation.  The sponsor has provided the safety profiles of 5757 studied subjects treated for GERD, esophagitis and dyspepsia with 10 mg-40 mg doses over a duration between 1 day-12 weeks (short-term).       Finally, the sponsor has provided two post-marketing surveillance databases of voluntary reports of adverse events. Of these one is the SafeTNet database related to marketing of the enteric coated prescription formuation.  Until 6/30/98 this database accumulated 15,835 AEs that represent 7,344 unique patient cases. The other database has been generated from marketing of the Omeprazole-Magnesium formulation for prescription use in Sweden after February 1998 until December 1999.  This database contains a total of 219 voluntarily contributed AE reports superimposed on a background of 11.6 million prescriptions.

## OTC Trials (n=8,179)

**Brief exposure to drug **
**Short term monitoring of AEs**
**Rare AEs not detectable **
**Small n of ages 12-17 (n=105)**
**Small n of Asian Americans (n=48)**

**Notes:**
OTC Trials  (n=8,179) 
Safety information gleaned from the OTC-Omeprazole-Mg Clinical trials is limited by the following characteristics:
First, there was brief exposure to the drug 
Second, there was Short term monitoring of AEs 
Third, the relatively Small number of subjects preclude comprehensive assessment of rare AEs since these may not be detectable in this size group of omeprazole exposed individuals.
It has to be pointed out that there was negligible representation of specific demographic groupings in these studies.  In particular, only 105 of adolescents ages 12-17 were exposed to omeprazole in actual usage studies)
Second, there was negligible representation of Asian Americans (48 subjects, 1%).  This may be relevant to the observation that this demographic group has a higher percentage than most other groups of people who are ‘slow metabolizers’ of omeprazole, a point that I will discuss later.

## OTC Omeprazole Side-effects

**OTC AEs similar to Rx AEs**
**Headache (439 cases),  Infection (190 cases), Diarrhea (167 cases)**
**Serum sickness (1 case),  urticaria (4 cases) and elevations of AST (7 cases) **
**No dose-related differences**
**Drug discontinuation - headache n=10; rash n= 3**
**2 deaths unrelated to drug**

**Notes:**
OTC Omeprazole Side Effects
The Findings in the OTC Omeprazole-Mg Clinical Trials are that
The Profile of common AEs is similar to the enteric coated prescription formulation
The most common AEs included headache (439 cases, 5%)  infection (190 cases, 2%) and diarrhea (167 cases, 2%)
In the database there are Cases of drug-related AEs included serum sickness (1 case),  urticaria (4 cases) and elevations of AST (7 cases), suggesting that these side-effects are not exceedingly rare.
There are no apparent dose-related differences in common AEs (when 10 mg was compared to  20 mg).
Causes for drug discontinuation in these studies included headache ( 10 subjects) and rash (3 subjects) 
The 2 deaths which occurred were unrelated to omeprazole

## Short Term Toxicity

**Hepatic**
**Agranulocytosis/marrow suppression**
**Angioedema/anaphylaxis**
**Drug - Drug interactions****	****	****	****	****	****	****	****	****	****	****	****	**

**Notes:**
Short term Toxicity - 4 databases

In synthesizing the 4 different sources of information concerning the safety profile of short-term omeprazole exposure, a number of toxicities have emerged as points for this discussion.  They are:
Hepatic toxicity/Liver Damage
Agranulocytosis/marrow suppression
Angioedema/anaphylaxis 
and 
Drug - drug interactions								

## Liver Injury

**9 trials (n=1409); 1-60 weeks**
**Toxicity not dose dependent**
**Most abnormalities are mild and transient**

**Notes:**
Liver Injury

The sponsor has provided a Liver function assessment that was performed in 4 US and 5 non-US clinical trials.  These studies included a total of 1409 patients.   Treatment duration with omeprazole lasted between 1-60 weeks.  Analysis enables estimate of incidence of association with drug	                   
Findings of these studies indicate that 
LFT abnormalities are not dose dependent and
Most LFT abnormalities are mild, transient, and not related to duration of treatment 

## Hepatitis Incidence

**Summary: Between 2/1000 and 5/1000 treated patients developed LFT abnormalities **_**>**_** 3X normal**

**Notes:**
		Hepatitis Incidence
As can be seen a few patients with liver injury were detected in the clinical trials.  
Transaminase elevations exceeded 3 times the upper limit of normal in 5 patients in the US trials and 1 patient in the non-US trials  with respective incidences of 0.58% and 0.18%.  
Not unexpectedly, the incidence of milder elevations of transaminases in both groups of studies was higher.  This finding supports the conclusion that a there is a spectrum of omeprazole associated transaminase elevations associated with omeprazole exposure. 
The studies revealed that Between 2/1000 and 5/1000 treated patients developed LFT abnormalities consistent with hepatitis.

## Liver Toxicity Post-Marketing

**SafeTNet**
**33 Fatal Cases**
**2  - no other explanation of causality (‘A’ rating)**
**227 non-fatal Serious Cases**
**4  - assigned an ‘A’ rating **
**2 developed toxicity after rechallenge  **
**FDA Adverse Event Reporting System (AERS)**
** ****2 liver transplants**

**Notes:**
Liver Toxicity Post-marketing (SafeTNet and AERS)

In the post-marketing data base SafeTNet there were
33 fatal cases - 2 which were assigned an ‘A’ rating.  This rating suggests a high probability of omeprazole toxicity since no other explanation of causality could be identified.
227 SAEs - Of these 4 were assigned an ‘A’ rating.  It should be pointed out that 2 of these 4 cases redeveloped hepatocellular necrosis after drug rechallenge demonstrating the unequivocal linkage to omeprazole   
According to the FDA Adverse Event Reporting System (AERS)] 2 of 57 domestic toxic liver events linked to omeprazole have required liver transplantation.
Therefore the range of liver damage associated with omeprazole rarely includes individuals who have developed severe toxicity and organ failure.  Unfortunately, the incidence of omeprazole linked irreversible liver damage, hepatic failure and liver related death cannot be extrapolated from a voluntary reporting database such as SafeTNet

## Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome

**Variable  time between exposure and onset of symptoms **
**49 SafeTNet cases **
**2 assigned an ‘A’ rating (1 fatal, 1 non-fatal)**

**Notes:**
Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome

With regards to Omeprazole Associated Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome (SJS)
There are Variable  time intervals between drug exposure and onset of symptoms 
In the post-marketing database there are 49 SafeTNet cases of this form of skin toxicity -  2 have been assigned an ‘A’ rating (1 fatal, 1 non-fatal). The nonfatal case redeveloped skin lesions upon drug  re-challenge showing the strong linkage to the drug.

## White Blood Cell SuppressionIncidence

**US trials **
**Granulocytopenia ****	****	****0.2 % - 0.7%**
**Leukopenia ****	****	****	****0.9 % - 1.5%****	****	**
**Intensive Medical Monitoring Program (New Zealand****)**** **
**Granulocytopenia ****	****	****0.03%**
**Aplastic Anemia ****	**** ****	****0.01%**

**Notes:**
White Blood Cell Suppression Incidence
The Incidence of White Blood Cell Suppression by Omeprazole is high enough to be detectable in relatively small clinical trial populations.    With regards to Granulocytopenia, in US short-term trials that have been analyzed the incidence was 0.2 % (1/657 subjects) and in US long-term trials it was 0.7 % (2/275 subjects).   For Leukopenia, the incidence in US short-term trials was 0.9 % (6/657 subjects) and in US long-term trials 1.5 % (4/275 subjects)		

Related to these observations, the Intensive Medical Monitoring Program in New Zeland in a 1 year followup of Omeprazole treated patients revealed that 0.03% (3 cases) developed Granulocytopenia and 0.01% (1 case) developed aplastic Anemia.

## White Blood Cell Suppression SafeTNet

**26 fatalities**
**5  assigned an ‘A’ rating**
**96 serious non-fatal cases **
**35 assigned an ‘A’ rating**
**Summary**
**Granulocytopenia incidence -  0.3-5 per thousand**
**Rare cases of fatal agranulocytosis**

**Notes:**
White Blood Cell Suppression (SafeTNet)

The post-marketing database SafeTNet has revealed that there are 
122 reported cases of omeprazole linked white blood cell suppression.  These include 26 fatalities.  Of the 26 fatal cases - 5  were assigned an ‘A’ rating
Of the 96 serious non-fatal cases - 35 were assigned an ‘A’ rating
In Summary
Significant Bone Marrow suppression associated with granulocyte counts <1.5X109/liter occurs with an incidence of between 0.3/1000 and 5/1000
Rare cases of fatal agranulocytosis have been reported

## Hypersensitivity 

**Clinical Trials**
- 	**Urticaria ****	****	****	****	****    1-2/1000 **
**New Zealand Monitoring**** ****	**
**	****Angioedema/Urticaria****	****	****    0.46/1000**

**Notes:**
		Hypersensitivity
As is the case of some of the other adverse events associated with  omeprazole exposure Hypersensitivity Reactions have occurred in Clinical Trials of the prescription formulation
In these trials
There were 48 cases of angioedema/anaphylaxis 
There were 3 fatalities associated with drug hypersensitivity
More commonly, the incidence of urticaria has ranged between 1 and 2 per 1000

Similarly, the reported incidence of hypersensitivity reactions including angioedema/urticaria in omeprazole users from the Intensive Medicines Monitoring Program (New Zealand; n=17,365 subjects) was 0.46 per 1000 patients

## Hypersensitivity (SafeTNet) Serious Adverse Events 

**Angioedema/Anaphylaxis n=134 **
**7 fatal **
**9 non-fatal assigned an ‘A’ rating**

**Notes:**
Hypersensitivity (SafeTNet) Serious Adverse Events

Not surprisingly, in the postmarketing SafeTNet database
There were 134 cases of angioedema and anaphylaxis  (48 cases were in clinical trials) 
7 of these 134 cases were fatal 
9 non-fatal cases were assigned an ‘A’ rating.
Features of ‘A’ rated cases included rapid onset of symptoms after drug exposure, reappearance of symptoms after rechallenge with omeprazole, and idiosyncratic reactions not predictable before first exposure to drug

## Hypersensitivity

**1/2000** - 	**Urticaria, Angioedema, ****	****	****Wheezing or Anaphylaxis  **

**Notes:**
		Hypersensitivity

In summary, immediate hypersensitivy reactions which include urticaria, angioedema, wheezing and anaphylaxis are linked to omeprazole exposure in approximately 1 per 2000 individuals

## Swedish Post-Marketing 1998-1999 Voluntary Reporting

**219 AEs /11.6 million Rx**
**25 serious non-fatal and 2 fatal **
**Hypersensitivity reactions**
**Liver toxicity**
**Toxic Epidermal Necrolysis**
**Interstitial nephritis**
**Bone Marrow Suppression**

**Notes:**
Swedish Post-Marketing 1998-1999 Voluntary Reporting
Omeprazole-Mg has been used as a prescription drug in Sweden since February 1998.  In  the  voluntary reporting system the safety findings are as follows:
Before 12/31/99 there  were 219 voluntary reports from a background of 11.6 million prescriptions; 
In this database the AE profile is similar to the profile of the enteric coated formulation 
25 of the AEs have been serious non-fatal cases and 2 were fatal cases
Reported Hypersensitivity reactions include angioedema , urticaria and anaphylactic shock and Liver toxicity reports include hepatic failure, cholestasis and increased liver enzymes 
Other serious AEs include Toxic Epidermal Necrolysis and Interstitial nephritis
Finally, cases of Agranulocytosis, Pancytopenia and Purpuric thrombocytopenia have been reported.

## Swedish Post-Marketing 1998-1999  Summary

**  ****                                               **
**No apparent differences between safety profiles of enteric coated prescription formulation and magnesium formulation**

**Notes:**
Swedish Post-Marketing 1998-1999 Summary

Although

Substantial differences between the safety profiles of the enteric coated prescription formulation of Omeprazole and Omeprazole-Magnesium have not emerged  

It should be pointed out that Subtle differences in formulation-associated risk to develop rare adverse events cannot be measured because of undefined reporting biases and the relative short time that Omeprazole-Mg has been marketed

## Effects on Drug Clearance

**CYP2C19  “Slow Metabolizers”**
**	****	****3 % Caucasians****	****	****	****15 % Asians**
**Aging**
**Liver disease**

**Notes:**
	Effects on Drug Clearance
Omeprazole is metabolized into an inactive metabolite by the liver cytochrome P450 isoenzyme CYP2C19
An important influence on Omeparzole Clearance is
The presence of a Polymorphism of the CYP2C19 isoform.  This genetic characteristic is associated with loss of activity of the isoenzyme and the ‘slowed metabolism’ of omeprazole  
Whereas  the “slow metabolizer” homozygous genotype (SM/SM) is identified in only 3 % of Caucasians it is present in 15 % Asians;       
Other factors which decrease drug clearance are aging  and Liver disease.    
A reduction in clearance of omeprazole may be linked to 2 effects. First, a longer circulating half-life of the drug and second, increasing circulating drug levels at steady state.  Because of the relatively short half-life of omeprazole, modest effects on clearance usually have small effects on circulating drug levels.

## Drug-Drug Interactions

**Increased Absorption ****	**
**Digoxin, nifedipine (10% -26% increase)**** **
**Decreased Absorption **
**Ketoconazole, itraconazole (80% decrease)**
**Inhibition of CYP2C19 and reduced clearance **
**Diazepam, phenytoin, R-warfarin, tolbutamide (10-55% decrease) **
**‘****Slow Metabolizers’ or people with underlying medical conditions may have pronounced changes**

**Notes:**
		Drug-Drug Interactions
Alterations of Activities of other drugs by Omeprazole occur by 2 distinct mechanisms. One of these  - Changes of drug absorption - occurs due to effects of the PPI on gastric luminal pH.               
Pertinent to this mechanism Increased absorption of Digoxin and Nifedipine ranging between 10%  and 26% increases have been observed in study subjects.   It should be pointed out that certain individuals, such as those with renal failure, are susceptible to digoxin toxicity, even after modest changes in blood levels.   In the opposite direction, decreased absorption of the antifungals Ketoconazole, Itraconazole by as much as 80% during treatment with omeprazole has been observed.	
The second mechanism by which omeprazole interacts with some other drugs is through the Inhibition of CYP2C19 leading to their reduced clearance.   Drugs in which also are cleared by CYP2C19 include Diazepam, Phenytoin, R-warfarin, and Tolbutamide.  During omeprazole treatment, decreases in clearance of these drugs  in study subjects have ranged between 10-55%. In the case of diazepam, an omeprazole-induced reduction of this magnitude may be clinically significant in individuals who are particularly susceptible, such as those with liver disease.    
Although omeprazole reduces clearance of these drugs only modestly in normal subjects, the potential for more pronounced alterations in individuals who are “slow metabolizers” taking multiple drugs in which alternate clearance pathways have been saturated or in individuals with underlying medical conditions such as liver disease has not been ruled out.

## Adolescents

**Not approved for Rx use under age 18**
**2% of total Rx in 11- 20 year old age group**
**Not included in Clinical Rx trials**
**Only 100 OTC study subjects under age 18**
**17% exceeded 10 day limit**
**Only 39 cases in SafeTNet**

**Notes:**
Adolescents
It needs to be emphasized that with regards to adolescents:
Omeprazole is not approved for prescription use in pediatric patients under age 18
Furthermore, only 2% of prescriptions in the US are dispensed to individuals in the 11 - 20 year old age range, mostly in an off-label manner
Subjects under age 18 were excluded from most clinical studies of the prescription formulation 
Only 100 subjects received Omeprazole-Mg in OTC Actual Use studies
17% of adolescents in these studies exceeded the labeled 10 days limit of omeprazole administration
Finally the SafeTNet only contains 39 cases of adolescents

## Safety in Adolescents

**Age related responses not studied**
**Age related toxicities not ruled out**

**Notes:**
Safety in Adolescents

From this it can be asserted that 
Age related susceptibility to omeprazole toxicity has not been ruled out.   Based on the very limited database in adolescents it is not possible to draw final conclusions about the relative safety of omeprazole in adolescents

## Embryo-Fetal Damage

**Not approved for Rx during pregnancy**
**Rabbit embryo-fetal lethality**
**Reduced rat fetal weights**
**Rat offspring reduced survival/growth                 ****	****and slowed behavioral development**
**Substantial human use has not revealed ‘signal’**
**Need prospective or nested case control studies**

**Notes:**
	Embryo-fetal damage
Currently, Omeprazole is not approved for prescription use during pregnancy.  There are a number of concerns regarding the use of omeprazole during pregnancy.  These include the following points:
The drug is Associated with embryo-fetal lethality in rabbits and reduced fetal weights in rats
In some experiments the drug has been found to be clastogenic.  This will be discussed later on.  
Nonetheless, voluntary reporting of females of childbearing age who have been issued 14% of the total prescriptions in the US before, during and after pregnancy has not revealed a ‘signal’ consistent with human embryo-fetal toxicity
With these observations, there is a need for Prospective or nested case control studies in pregnant women to confirm safety of embryo-fetal exposure.

## Adverse Events - Long-Term Exposure

**Masking and/or delay in dx of GERD complications and malignancy**
**Tumorigenic potential of drug-induced hypergastrinemia and drug related genotoxicity**
**Exaggerated rebound of gastric acid secretion**

**Notes:**
Adverse Events - Long-term exposure
Let me switch gears to talk about safety issues that surround long-term exposure  of omeprazole defined as exposure of more than 12 weeks and in some cases longer than a year.
These include Masking and/or delay in diagnosis of GERD related complications and/or conditions which require medical treatment.  These include Barrett’s esophagus, Advanced stages of erosive esophagitis, esophageal dysplasia and adenocarcinoma  of the esophagus or stomach.
A second issue is the undefined  tumorigenic potential of drug-induced prolonged hypergastrinemia  and genotoxic properties related to the drug
Finally, a concern has been raised concerning the Potential for rapid and/or exaggerated rebound of gastric acid secretion after cessation of treatment that is tied to recurrence of reflux symptoms and/or mucosal inflammatory changes.

## Concern on Long-Term OTC Use

**Proposed label - No warning on long-term intermittent use **
**Actual Use studies - Over 10 days use **
**Maximal acid suppression - after 2-3 days of daily 20 mg doses **
**Many subjects had GERD. **

**Notes:**
Concern on Long-term use

As I alluded to it is likely that long-term use of Omeprazole will be common among undifferentiated OTC consumers with heartburn since:
The proposed labeling does not warn against long-term intermittent use 
Actual Use studies revealed that Continued treatment occurred beyond the upper 10 day limit stated in the label in a large percentage of those who use the drug to prevent heartburn
Based on the pharmacodynamic properties of omeprazole multiple doses of the drug are required for maximal acid suppression
Finally, The History of symptoms of many of the OTC study recruits  was consistent with GERD, a chronic recurrent condition

## Masking of Gastric Malignancy

**49 gastric malignancy cases in SafeTNet**
**4/49 delay in diagnosis**
**Reasons for masking**
**	****Temporary alleviation **
**	****Improvement in appearance of lesions**

**Notes:**
Masking of Gastric Malignancy

Moreover the concern about masking of underlying disease is justified from a number of anectodal voluntary postmarketing SafeTNet reports which indicate that delay in diagnosis of gastric malignancy can occur due to temporary alleviation of symptoms or improvement in appearance of gastric lesions. In 4/49 cases of omeprazole linked gastric adenocarcinoma there was a 1-12 month delay in diagnosis after treatment was started.

## GERD Complications 

**1. Barrett’s esophagus  1-6%**
**Symptoms not distinguishable from GERD**
**Medical management - endoscopic surveillance  for dysplasia/cancer**
**2. Erosive esophagitis (advanced stages) 2.4-47%**
**Medical management - aggressive suppression of gastric acid secretion **

**Notes:**
GERD Complications 

It should be emphasized that the incidence of GERD complications is not trivial.  Complications include:
Barrett’s esophagus  which occurs at an incidence of 1-6% of people who use antacids for longstanding chronic heartburn, depending on the published study.
It is important to note that symptoms associated with Barrett’s esophagus are  not distinguishable from GERD
medical management includes regular endoscopic surveillance  for dysplasia/cancer
A different complication of GERD is the composite of advanced stages of Erosive esophagitis (Grades II or greater) whose incidence is 2.4-47% of individuals with longstanding histories of GERD.  These individuals are at increased risk to develop clinically significant strictures and other fibrotic changes.
Currently, their medical management includes aggressive pharmacological suppression of gastric acid secretion 

## GERD Complications

**3. Barrett’s esophagus with dysplasia < 1%**
**Delay in dx prevents surveillance **
**4. Esophageal adenocarcinoma <1%**
**Delay in dx reduces chance of survival**

**Notes:**
GERD Complications 
Another GERD complication is
Barrett’s esophagus with dysplasia that occurs in < 1% of people with chronic heartburn
Medical management in these individuals includes early recognition followed by frequent surveillance and/or surgery
 Finally, esophageal adenocarcinoma occurs  <1% of undifferentiated GERD sufferers.
Medical management in these people includes chemotherapy, radiotherapy and/or surgery in selected cases

## GERD: Standard of Medical Care*

**Early MD referral with:**
**Dysphagia or odynophagia****	**
**Persistent symptoms despite treatment**
**Hematemesis melena, rectal bleeding or anemia**
**Weight loss and/or anorexia**
**Unexplained chest pain****	****	****	****	****	****	****	****	****	****	****	****	**

**Notes:**
GERD: Standard of Medical Care

Because of the complications that I have mentioned effective triage of individuals with GERD who require further diagnostic testing plays an important role in their management.  The current standard of medical care includes the following features:
Early physician referral is recommended* for individuals with one or more of the following:
Dysphagia or odynophagia	
Persistent symptoms despite treatment
Hematemesis melena, rectal bleeding or anemia
Weight loss and/or anorexia
Unexplained chest pain													

## GERD: Standard of Medical Care*

**Early MD referral with:**
**Chronic cough, hoarseness, asthma**
** **
**Chronic symptoms in patients at high risk for Barrett’s Esophagus **
**Need for continuous chronic therapy**
***1999 Practice Guidelines, American College of Gastroenterology**

**Notes:**
GERD: Standard of Medical Care (Cont.)

Chronic cough, hoarseness, Asthma
 Chronic symptoms in patients at high risk for Barrett’s Esophagus 
Need for continuous chronic therapy
Therefore, early physician evaluation of individuals with GERD who have features that put them at risk for underlying diseases is part of the current standard of medical care in the US.   Endoscopic evaluation may be warranted in many of these individuals.

*1999 Practice Guidelines, American College of  Gastroenterology

## GERD Management Summary

**Physician referral after a failed treatment course or recurrence of GERD symptoms after cessation of therapy is thought to provide an important margin of safety to exclude a significant underlying disease(s)****	****	****	****	****	**

**Notes:**
GERD Management Summary

In summary

Physician referral after a failed treatment course or recurrence of GERD symptoms after cessation of therapy is thought to provide an important margin of safety to exclude a significant underlying disease(s)							

## GERD Management

**Consistent with this perspective the sponsor has said:**
**...‘In order to avoid the risk of possible complications that may occur with long-standing and persistent heartburn, consumers should be made aware of the indications, dosage and duration of therapy of over-the counter heartburn medications they intend to use.  In addition, they should have a clear understanding when to seek medical attention.’  **

**Notes:**
GERD Management 
Consistent with this perspective the sponsor has made the following statement:
...‘In order to avoid the risk of possible complications that may occur with long-standing and persistent heartburn, consumers should be made aware of the indications, dosage and duration of therapy of over-the counter heartburn medications they intend to use.  In addition, they should have a clear understanding when to seek medical attention.’

## Is Omeprazole Tumorigenic  in Humans?

-  **Issues of concern**
**Trophic effect of hypergastrinemia **
**Potential for exaggerated growth promoting effects in ***H. Pylori*** infected individuals**
** ****Genotoxicity**

**Notes:**
Is Omeprazole Tumorigenic  in Humans?

Issues of concern that have been raised concerning a potential carcinogenic effect of omeprazole in a large population of chronic users are based on the following possible mechanisms:
Omeprazole induced hypergastrinemia has a trophic effect on gastric Enterochromaffin cells as well as other cell lineages both within and outside the GI tract
There is a Potential by omeprazole induced hypergastrinemia to cause exaggerated growth promoting effects in the gastric mucosa  of H. Pylori infected individuals
Finally, the Genotoxic properties of Omeprazole in susceptible cells both within and outside the GI tract may promote carcinogenesis

## Omeprazole Induced Hypergastrinemia

**2-4 fold increases in serum gastrin concentrations are common**
**Elevated levels reverse upon stopping **
**Increases not observed with ‘low dose’ H-2 receptor antagonists**
**Pronounced hypergastrinemia occurs in ‘outliers’**

**Notes:**
Omeprazole Induced Hypergastrinemia
Omeprazole Induced Hypergastrinemia is characterized in the following manner:
Many individuals manifest a 2-4 fold increase in serum gastrin concentration above baseline during chronic administration of omeprazole which reverses your cessation of treatment. Increases of this magnitude are not observed during administration of  ‘low dose’ H-2 receptor antagonists that are used to treat heartburn over-the-counter.
A small percentage of individuals develop pronounced responses with greater than 4 fold increases of serum gastrin concentrations, some well above the upper limit of normal.  These individuals may be particularly vunerable to drug-related cancer risk

## Omeprazole Induced Hypergastrinemia

**Serum gastrin increase may be pronounced when:**
**H. pylori infection**
**CYP2C19 polymorphism (SM/EM or SM/SM) **
**High dose and increased frequency of treatment**
**Low pretreatment gastric acid secretion state**

**Notes:**
Omeprazole Induced Hypergastrinemia (Cont.)

Factors which may increase serum gastrin responses to omeprazole in some individuals include:
H. pylori infection
the CYP2C19 polymorphism including both the heterozygous (SM/EM) or homozygous (SM/SM genotypes) 
High dose and increased dosaging frequency of  omeprazole and
Medical/physiological conditions in which there is a reduced level of pretreatment gastric acid secretion

## Genotoxicity

**In vivo and in vitro clastogenic effects in mouse and human bone marrow cells**
**Chromosomal aberrations in human lymphocytes**
**Increased sister chromatid exchanges in peripheral lymphocytes of treated subjects **
**(C. Thompson et al, 1991).  Not confirmed**
**DNA mutagenicity as tested by the Ames Salmonella typhimirium test consistently negative**

**Notes:**
Genotoxicity

The genotoxic potential of omeprazole is predicated on the following observations
In vivo and in vitro clastogenic effects have been noted in drug-exposed mouse and human bone marrow cells
Chromosomal aberrations in omeprazole-exposed human lymphocytes have been noted
Increased sister chromatid exchanges in peripheral lymphocytes of treated subjects have been reported in one set of measurements  (C. Thompson et al, 1991).  Similar reports have not been forthcoming
Despite these findings DNA mutagenicity testing as measured by the Ames Salmonella typhimirium test has been consistently negative

## GenotoxicitySummary

**Due to possible genotoxicity, long-term exposure may be linked to increased risk of malignancy**

**Notes:**
Genotoxicity(Cont.)

Taken together, in the face of inconsistently positive results that Omeprazole has clastogenic properties it is not possible to rule out genotoxicity associated with long-term exposure to the drug that  may be linked to an increased risk of malignancy

## Difficulties in Determining Carcinogenicity of Omeprazole

**Limited number of subjects followed for longer than 1 year **
**Lack of long-term prospective or nested cohort studies to track patients **
**Detection of malignancy - long lag phase **
**High background rates of malignancies - drown out weak ‘signals’**

**Notes:**

Difficulties in Determining Carcinogenicity of Omeprazole

Taking a step back and analyzing the carcinogenic potential of omeprazole in humans there are a number of significant limitations. These include:
The size of controlled studies of  individuals treated for longer than 1 year are small, precluding detection of rare drug-related tumors
There is a lack of prospective or nested cohort studies to track patients treated with omeprazole over a long period of time
Detection of malignancy is limited by a predicted long lag phase after drug exposure
In some cases high background rates of certain GI malignancies (such as those associated with colorectal and pancreatic tumors) are expected to drown out weak ‘signals’

## Difficulties in Determining Carcinogenicity of Omeprazole

**SafeTNet  - voluntary reporting **
**Lack of definition of high risk groups. Such subsets may be diluted by groups not at increased risk **

**Notes:**
Difficulties in Determining Carcinogenicity of Omeprazole
(Cont.)

SafeTNet relies on voluntary reporting which is not comprehensive 
Finally, there is a lack of definition of groups that may be especially vunerable to the carcinogenic effect of omeprazole. Such subsets of the population may be diluted by individuals who are not at increased risk for malignancy when exposed to the drug

## Evidence to Date of CarcinogenicitySummary of Clinical Studies, SafeTNet and Literature

**ECL cell hyperplasia in humans, unlike rats, not linked to carcinoid tumors**
**No apparent causal relationship with carcinoid tumors and other GI malignancies**
**Contribution in H. Pylori infected subjects to the development of gastric mucosal atrophy, intestinal metaplasia and dysplasia not apparent**

**Notes:**
	Evidence to Date of Carcinogenicity
Summary of Clinical Studies, SafeTNet and Literature

Taking these deficiencies into account, at present, based on a composite of the Clinical Studies, SafeTNet data and the literature to date
The development of Omeprazole induced ECL cell hyperplasia in humans, unlike rats, is not linked to progression to carcinoid tumors
There is no apparent causal relationship between omeprazole and carcinoid tumors, gastric adenocarcinoma, colorectal adenocarcinoma and other malignancies
In H. Pylori infected subjects a clinically significant contribution by omeprazole to the development of gastric mucosal atrophy, intestinal metaplasia and dysplasia is not apparent

## Rebound of Gastric Acid Secretion

**Cessation of treatment associated with rapid reappearance of erosive esophagitis**
**Acid rebound reflected by increases in both basal and pentagastrin stimulated acid secretion**
**Acid rebound is self-limited**

**Notes:**
	Rebound of Gastric Acid Secretion

Finally, there has been concern about Rebound of Gastric Acid Secretion After Cessation of Omeprazole.  This is based on the following points:
First, Cessation of treatment is associated with rapid reappearance of inflammatory changes in individuals with erosive esophagitis
Second, Acid rebound is reflected by increases in both basal and pentagastrin stimulated acid secretion. This effect is Variable and is not unique to PPIs since it is also linked to ‘full dose’ H-2 receptor antagonists (doses recommended for the treatment of peptic ulcers)
Lastly, Acid rebound is self-limited after discontinuation of treatment with omeprazole

## Rebound of Gastric Acid Secretion

**Whether acid rebound plays a role to extend usage has not been studied**
***H. Pylori***** may influence the development of acid rebound **
**Pronounced acid rebound may not be detected in small studies**

**Notes:**
Rebound of Gastric Acid Secretion (Cont.)

No information has been provided by the sponsor to determine whether acid rebound plays a role in some subjects to extend the duration of continuous OTC self-medication with omeprazole.   Therefore, it is not possible to assess at this time whether conditions which affect acid secretion such as H. Pylori may influence the development of acid rebound after cessation of omeprazole treatment
In addition, pronounced acid rebound in a subset of susceptible individuals cannot be excluded. Such a phenomenon would not necessarily be detected in studies which enroll small numbers of test subjects

## Summary of Safety Issues

**Range of liver toxicities **
**Toxicity is usually mild, self-limited and reversible**
**Significant hepatocellular necrosis occurs rarely and has been linked to a few deaths **
**Toxic Epidermal Necrolysis and Steven-Johnson Syndrome**
**While rare, some cases have been linked to death**

**Notes:**
	Summary of Safety Issues

In conclusion, omeprazole-Mg is associated with 
a range of liver toxicities - Toxicity is idiosyncratic, usually mild, self-limited and reversible upon drug withdrawal. However, the drug causes significatly hepatocellular necrosis in a small percentage of individuals and has been linked to a few deaths. Causality of significant hepatocellular  damage has been confirmed in a few cases by rechallenge with omeprazole
Omeprazole is also associated with Toxic Epidermal Necrolysis and Steven-Johnson Syndrome- Although very rare, some cases have been linked to death

## Summary of Safety Issues

**Marrow suppression **
** ****Life-threatening suppression is rare **
**Drug hypersensitivity- **
**Causality has been supported by drug rechallenge**
**Incidence of hypersensitivity may be as high as 0.5 per 1000**

**Notes:**
	Summary of Safety Issues (Cont.)

The drug has been linked to Agranulocytosis and other disorders of marrow suppression- Life-threatening suppression of leukocytes by  omeprazole is rare. Usually, drug-induced marrow suppression is reversible upon drug withdrawal 
Drug hypersensitivity- In some cases in which symptoms of urticaria,wheezing, rash anaphylaxis and/or angioedema after omeprazole exposure have appeared, causality of drug hypersensitivity has been proven by drug rechallenge. The incidence of hypersensitivity responses have been detected in clinical trials and may be as high enough as 0.5 per 1000 users of omeprazole

## Summary of Safety Issues

**Even if SAEs and the fatalities related to them are rare, in a background of millions of OTC consumers per year a significant number of these events are expected.  **
**For example, if there are 10 million OTC courses of Omeprazole - Mg issued in a**** ****year and the rate of an SAE is 1/10000, then 1000 SAEs are predicted to occur****	****	**

**Notes:**
	Summary of Safety Issues

Even if SAEs and the fatalities related to them are rare, in a background of millions of OTC consumers per year a significant number of these events are expected.  For example, if there are 10 million OTC courses of Omeprazole - Mg issued in a year and the rate of an SAE is 1/10000, then 1000 SAEs are predicted to occur		

## Summary of Safety Issues 

**Adolescent Subjects **
**Omeprazole is not approved for Rx use in adolescents. **
**The number of study subjects in this age group are is small**

**Notes:**
	Summary of Safety Issues (Cont.)

Pediatric subjects - Currently, Omeprazole is not approved for prescription use in adolescents. The number of clinical study subjects in this age group and the numbers of AEs reported in the post-marketing database are too small to determine whether adolescents have different susceptibilities to develop rare toxic events linked to omeprazole

## Summary of Safety Issues

**Pregnancy**
**Categorized as a “ Class C” drug because of embryo-fetal and postnatal toxicity in animal models. **
**The drug has clastogenic properties **

**Notes:**

	Summary of Safety Issues (Cont.)

Pregnancy - Currently, Omeprazole is categorized as a “ Class C” drug because of embryo-fetal toxicity in an animal model. In addition, there are concerns about the clastogenic properties of the drug.  Nonetheless, off-label use has not demonstrated omeprazole-linked loss of fertility or teratogenicity in humans 

## Summary of Safety Issues Long-term use 

**GERD complications/diseases may be masked    **
**Including Barrett’s esophagus, advanced erosive esophagitis, esophageal dysplasia, esophageal cancer and gastric cancer**
**May induce significant hypergastrinemia and/or manifest genotoxicity - Implications not fully known**

**Notes:**
Summary of Safety Issues - Long Term Use
With regards to long-term exposure 
Omeprazole May mask clinically significant GERD complications/diseases which require early diagnosis and specific medical management.  These include Barrett’s esophagus, advanced erosive esophagitis, esophageal dysplasia, esophageal cancer and gastric cancer
The drug May induce significant hypergastrinemia and/or manifest genotoxicity in some individuals - Hypergastrinemic responses to Omeprazole may be more pronounced in those with H. Pylori infection or in “ Slow metabolizers”. However, based on voluntary reporting a tumor association with Omeprazole administration has not emerged. The possibility that there are oncogenic effects of the drug in susceptible groups who are exposed to the drug for very long periods of time has not been ruled out

## Summary of Safety Issues Long-term use

**Rebound of Acid Secretion**
**Relapse of heartburn symptoms and/or esophageal inflammatory changes is predicted in some people with GERD**

**Notes:**
	Summary of Safety Issues (Cont.)

Rebound of Acid Secretion may encourage long-term usage in a subset of consumers - Upon cessation of treatment rapid relapse of heartburn symptoms and/or esophageal inflammatory changes is predicted in some individuals with GERD

## Safety:Risk Management

**Rx - relies on ‘learned intermediary’ to:**
**evaluate patient**
**recognize and manage drug toxicity**
**OTC - relies on labeling   **
**Can omeprazole safety concerns be addressed adequately through labeling?**

**Notes:**
		Safety: Risk Management
Taken together
The prescription use of omeprazole has relied on the presence of professional health care providers for patient assessment, triage for further diagnostic testing and recognition and management of significant drug toxicity 
In the OTC setting, there is no learned intermediary to enact these functions so that  safe and effective use entirely depends on effective consumer labeling

## Safety:Risk Management

-  **Concerns**
** ****Absence of physician supervision to recognize and manage serious toxicity**
** ****Appropriate triage of GERD patients**
** ****benefit in the absence of significant risk**
** ****safeguards to ensure physician referral**

**Notes:**
		Safety:Risk Management

We are concerned whether serious omeprazole Mg-induced toxicity will be recognized and effectively managed by OTC consumers without physician supervision

Furthermore, chronic empirical therapy prior to physician referral is inappropriate for a significant number of patients with GERD.  We are concerned whether Omeprazole -Mg can be targeted in an OTC setting to only those consumers for whom self-medication will have a meaningful benefit in the absence of a significant risk for serious adverse events.  Conversely, we are concerned whether there are adequate safeguards protecting those for whom physician referral is indicated to justify OTC approval.