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Clinical Safety Profile OTC Omeprazole Magnesium (Prilosec 1 TM )

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. Safety Profile Issues. Proposed Label - No warning on long-term intermittent use

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Clinical Safety Profile OTC Omeprazole Magnesium (Prilosec 1 TM )

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

  9. Liver Injury • 9 trials (n=1409); 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 > 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 n=134 • 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 1998-1999Summary • 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. 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. 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. 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 Barrett’s Esophagus • Need for continuous chronic therapy • *1999 Practice Guidelines, American College of Gastroenterology

  32. GERD ManagementSummary • 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 ayear 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 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. 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

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