Clinical Safety Profile OTC Omeprazole Magnesium (Prilosec 1 TM by kzl15411


									  Clinical Safety Profile
OTC Omeprazole Magnesium

         (Prilosec 1TM)
         October 20, 2000

       Mark Avigan, MD CM
   Division of Gastrointestinal and
     Coagulation Drug Products
             CDER, FDA                1
            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.

                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
            Outline of Talk (Cont.)

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

• Conclusions

    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)

         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)

     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                  7
        Short Term Toxicity

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

              Liver Injury

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

            Hepatitis Incidence

                                                  US            NON US
                                                  (n=853) %     (n=556)   %
   Transaminases < 3X upper limit of Normal
                                                   31    3.6      9       1.6
   Transaminases > 3X Upper limit of Normal
                                                    5    0.58     1       0.18
  Alkaline phosphatase
                                                   35    4.1      31      5.6
  Any LFT abnormality including serum
                                                   253   30      177      32
  bilirubin or isolated transaminase elevations

Summary: Between 2/1000 and 5/1000 treated patients
developed LFT abnormalities > 3X normal
       Liver Toxicity Post-Marketing
• 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
    Toxic Epidermal Necrolysis and
      Stevens-Johnson Syndrome

• Variable time between exposure and onset of
• 49 SafeTNet cases
  •2 assigned an „A‟ rating (1 fatal, 1 non-fatal)

    White Blood Cell Suppression

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%

White Blood Cell Suppression SafeTNet
 • 26 fatalities
    5 assigned an „A‟ rating
    96 serious non-fatal cases
    35 assigned an „A‟ rating
    Granulocytopenia incidence - 0.3-5 per thousand
    Rare cases of fatal agranulocytosis
Clinical Trials
 Urticaria               1-2/1000

New Zealand Monitoring
 Angioedema/Urticaria    0.46/1000

    Hypersensitivity (SafeTNet)
     Serious Adverse Events

• Angioedema/Anaphylaxis n=134
• 7 fatal
• 9 non-fatal assigned an „A‟ rating


1/2000 - Urticaria, Angioedema,
         Wheezing or Anaphylaxis

 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

Swedish Post-Marketing 1998-1999

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

 Effects on Drug Clearance

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

       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%
  • „Slow Metabolizers‟ or people with underlying medical
  conditions may have pronounced changes

• 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

     Safety in Adolescents

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

          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

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
 • Exaggerated rebound of gastric acid secretion

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.

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

          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

           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

  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
    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
      GERD Management

• 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
       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.‟                        33
Is Omeprazole Tumorigenic in

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

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‟

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
  • Low pretreatment gastric acid secretion state

• In vivo and in vitro clastogenic effects in mouse
  and human bone marrow cells
• Chromosomal aberrations in human
• 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                                     37

• Due to possible genotoxicity, long-
  term exposure may be linked to
  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‟
  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

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
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
• Acid rebound is self-limited

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

       Summary of Safety Issues
• Range of liver toxicities
  • Toxicity is usually mild, self-limited and
  • Significant hepatocellular necrosis occurs
    rarely and has been linked to a few deaths
• Toxic Epidermal Necrolysis and Steven-Johnson
  • While rare, some cases have been linked to
    death                                    44
    Summary of Safety Issues
• Marrow suppression
  • Life-threatening suppression is rare
• Drug hypersensitivity-
  • Causality has been supported by drug
  • Incidence of hypersensitivity may be
    as high as 0.5 per 1000

    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
  • The number of study subjects in this age
    group are is small

   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

       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

   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

    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?

    Safety:Risk Management

 • 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


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