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

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									  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.



                                                  2
                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
                                                     3
            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

                                                     4
    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)


                                               5
         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)


                                      6
     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


                                       8
              Liver Injury


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



                                              9
            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
                                                                          10
       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
                                                       11
    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)



                                                     12
    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%

                                              13
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
                                                14
             Hypersensitivity
Clinical Trials
 Urticaria               1-2/1000


New Zealand Monitoring
 Angioedema/Urticaria    0.46/1000




                                     15
    Hypersensitivity (SafeTNet)
     Serious Adverse Events

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




                                       16
        Hypersensitivity


1/2000 - Urticaria, Angioedema,
         Wheezing or Anaphylaxis




                                   17
 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

                                        18
Swedish Post-Marketing 1998-1999
            Summary


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



                                          19
 Effects on Drug Clearance

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



                                20
       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
                                                       21
                 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

                                            22
     Safety in Adolescents



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



                                     23
          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

                                               24
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


                                            25
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.


                                          26
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



                                            27
          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

                                             28
           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




                                             29
  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
                                          30
    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
                                                          31
      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)
                                      32
       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
         Humans?

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


                                        34
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‟


                                                 35
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

                                              36
              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                                     37
            Genotoxicity
               Summary

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



                                        38
   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‟
                                        39
  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

                                     40
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
                                                41
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


                                            42
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



                                               43
       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                                    44
    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

                                           45
    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
                                      46
    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


                                          47
   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


                                            48
       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

                                                 49
   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




                                           50
    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?

                                              51
    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


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