1. 1 Clinical Safety Profile OTC Omeprazole Magnesium (Prilosec 1 TM ) October 20, 2000 Mark Avigan, MD CM Division of Gastrointestinal and Coagulation Drug Products CDER, FDA

2. 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. 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. 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. 5 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)

6. 6 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)

7. 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 n=10; rash n= 3 2 deaths unrelated to drug

8. 8 Short Term Toxicity Hepatic Agranulocytosis/marrow suppression Angioedema/anaphylaxis Drug - Drug interactions

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

10. 10 Hepatitis Incidence Summary: Between 2/1000 and 5/1000 treated patients developed LFT abnormalities > 3X normal

11. 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. 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. 13 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%

14. 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. 15 Hypersensitivity Clinical Trials Urticaria 1-2/1000 New Zealand Monitoring Angioedema/Urticaria 0.46/1000

16. 16 Hypersensitivity (SafeTNet) Serious Adverse Events Angioedema/Anaphylaxis n=134 7 fatal 9 non-fatal assigned an ‘A’ rating

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

18. 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. 19 Swedish Post-Marketing 1998-1999 Summary No apparent differences between safety profiles of enteric coated prescription formulation and magnesium formulation

20. 20 Effects on Drug Clearance CYP2C19 “Slow Metabolizers” 3 % Caucasians 15 % Asians Aging Liver disease

21. 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. 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. 23 Safety in Adolescents Age related responses not studied Age related toxicities not ruled out

24. 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. 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. 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. 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. 28 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

29. 29 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

30. 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. 31 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

32. 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. 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. 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. 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. 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. 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. 38 Genotoxicity Summary Due to possible genotoxicity, long- term exposure may be linked to increased risk of malignancy

39. 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. 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. 41 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

42. 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. 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. 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. 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. 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. 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. 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. 49 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

50. 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. 51 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?

52. 52 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

53. 53