Clinical Safety Profile OTC Omeprazole Magnesium (Prilosec 1TM)

1
Clinical Safety ProfileOTC Omeprazole Magnesium
(Prilosec 1TM)

• October 20, 2000

Mark Avigan, MD CM Division of Gastrointestinal
and Coagulation Drug Products CDER, FDA
2
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.

3
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

4
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

5
Adverse Events - Short-term Exposure4 Databases

• OTC Clinical Trials
  n8179 daily 10 mg-20 mg
  doses 1-14 days
• Rx Clinical Trials
  n5757 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)

6
OTC Trials (n8,179)

• Brief exposure to drug
• Short term monitoring of AEs
• Rare AEs not detectable
• Small n of ages 12-17 (n105)
• Small n of Asian Americans (n48)

7
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 n10 rash n 3
• 2 deaths unrelated to drug

8
Short Term Toxicity

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

9
Liver Injury

• 9 trials (n1409) 1-60 weeks
• Toxicity not dose dependent
• Most abnormalities are mild and transient

10
Hepatitis Incidence
Summary Between 2/1000 and 5/1000 treated
patients developed LFT abnormalities gt 3X normal
11
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

12
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)

13
White Blood Cell SuppressionIncidence

• 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

14
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

15
Hypersensitivity
Clinical Trials Urticaria 1-2/1000 New
Zealand Monitoring Angioedema/Urticaria
0.46/1000
16
Hypersensitivity (SafeTNet) Serious Adverse
Events

• Angioedema/Anaphylaxis n134
• 7 fatal
• 9 non-fatal assigned an A rating

17
Hypersensitivity
1/2000 - Urticaria, Angioedema, Wheezing or
Anaphylaxis
18
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

19
Swedish Post-Marketing 1998-1999 Summary

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

20
Effects on Drug Clearance

• CYP2C19 Slow Metabolizers
• 3 Caucasians 15 Asians
• Aging
• Liver disease

21
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

22
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

23
Safety in Adolescents

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

24
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

25
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

26
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.

27
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

28
GERD Complications

• 1. Barretts 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

29
GERD Complications

• 3. Barretts esophagus with dysplasia lt 1
• Delay in dx prevents surveillance
• 4. Esophageal adenocarcinoma lt1
• Delay in dx reduces chance of survival

30
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

31
GERD Standard of Medical Care

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

32
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)

33
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.
34
Is Omeprazole Tumorigenic in Humans?

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

35
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

36
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

37
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

38
GenotoxicitySummary

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

39
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

40
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

41
Evidence to Date of CarcinogenicitySummary 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

42
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

43
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

44
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

45
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

46
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

47
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

48
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

49
Summary of Safety Issues Long-term use

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

50
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

51
SafetyRisk 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?

52
SafetyRisk 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

53
(No Transcript)