Clinical Perspective on Citizen Petition

1. Clinical Perspective on Citizen Petition NDAC / PADAC Joint Meeting Robert J. Meyer, MD Director, DPADP CDER / FDA May 11th, 2001

2. Clinical Perspective Important Considerations for OTC Switch: • The ability of the consumer to self-diagnose and/or self-manage • Safety and effectiveness for drug used in OTC setting (i.e., without a “learned intermediary”)

3. Clinical Perspective These important considerations are often addressed by: • OTC actual-use study; and/or • Label comprehension study

4. Clinical Perspective • Allegra, Claritin and Zyrtec are all antihistamines, all approved to treat allergic rhinitis • FDA accepts allergic rhinitis as an appropriate OTC indication, and • FDA accepts antihistamines as appropriate for OTC use • FDA has established appropriate OTC labeling for antihistamine products

5. Clinical Perspective Neither an actual-use study nor a labeling comprehension study is necessary for the OTC switch proposed FDA is not seeking advice on: • Allergic rhinitis as an OTC indication • On the effectiveness of Claritin, Zyrtec or Allegra in OTC setting

6. Clinical Perspective • Focus of FDA clinical presentation is on safety and how the safety experiences bear on the decision for OTC availability • FDA performed full safety review • NDA data • Post-marketing data (AERS) • Other sources

7. Safety Presentation • Elements of safety presentation: • NDA data • Standard safety data, cardiac safety evaluation, drug-interactions • Post-marketing experience • Case Review, Epidemiology • Focus for NDA on single ingredient compounds • AERS reports for include all formulations

8. Safety Presentation - Caveats • Safety review is not intended to be comparative of the three agents • Safety review will not attempt to rigorously compare to OTC antihistamines • Safety review will help define the safety experience with these agents individually

9. Safety Presentation - Caveats • Most definitive safety data are from NDA • Post-marketing data offers less definitive information about product safety • The use of epidemiology evaluations of AERS data can help place post-marketing data in perspective, but is not definitive

10. NDA Data Introduction • Claritin (loratadine) • approved for marketing April 12, 1993 • Zyrtec (cetirizine) • approved for marketing Dec. 8, 1995 • Allegra (fexofenadine) • approved for marketing July 25, 1996

11. NDA Safety Data • Numbers of Patients Exposed • Safety Experience in Clinical Trials • Cardiac Safety (in vitro, animals, human) • Drug Interactions

12. NDA Safety Data Introduction Why the focus on cardiac safety and drug-drug interactions? • Issues for Seldane (terfenadine): • ECG / repolarization effects (QT interval) • Cases of malignant arrhythmias (TdP) • Problem was clinically manifest due to drug-drug interactions • Similar issues with Hismanal

13. NDA Safety Data Introduction Cardiac Investigation of this potential for a new drug may include: • In vitro studies of ion (K+) channels and repolarization in isolated cardiac muscle • In vivo animal studies • Clinical data • e.g., high dose and drug interaction studies, clinical monitoring in clinical trials

14. Claritin NDA Database • In the NDA database for loratadine over 90,000 patients exposed • Adverse event profile was consistent for an antihistamine given for allergic rhinitis • No significant clinical safety signals in original NDA

15. Claritin NDA Database

16. Claritin NDA Database • Somnolence was dose-related, with reporting of 10% with 20 mg QD, 12% with 40 mg QD • Pediatric studies (6 - 11 years) showed similar AE profile • Nervousness, hyperkinesia, wheezing and abdominal pain also reported • No significant safety concerns at the time of approval

17. Claritin Cardiac Safety • In vitro testing (ion channel, myocardial cells) was negative • No QT or repolarization effects documented in animals • No significant cardiac AE’s seen in clinical trials (up to 160 mg) • No clinically meaningful effect on QTc documented in clinical studies

18. Claritin Metabolic Considerations • Loratadine metabolized by CYP3A4, 2D6 • Drug interaction studies with erythromycin, cimetidine and ketoconazole showed some increase in loratadine and desloratadine AUCs • No clinically significant impact • Renal and hepatic insufficiency decrease clearance

19. Zyrtec NDA Database • An Active metabolite of hydroxyzine • Over 3900 patients were treated in clinical trials with Zyrtec • Adverse event profile consistent with an antihistamine given for allergic rhinitis

20. Zyrtec NDA Database

21. Zyrtec NDA Database • Somnolence was dose-related • Other AEs reported in children at a rate higher than placebo in both doses: • abdominal pain, diarrhea, vomiting • somnolence in children 1.9% with 5 mg, 4.2% with 10 mg, placebo = 1.3% • No significant safety signals from original NDA

22. Zyrtec Cardiac Safety • In vitro testing (myocytes, ion channels) revealed no effects at relevant concentrations • No significant QT or repolarization effects seen in whole animals • No significant cardiac AE’s seen in clinical trials, including 6 times the recommended dose • 1 of 4 safety-exposure studies showed an effect on the ECG • 9.1 msec increase in QTC using Bazett’s correction

23. Zyrtec Metabolic Considerations • Renal excretion, the majority unchanged • No significant drug interactions • Renal impairment causes moderate decrease in clearance • Hepatic impairment causes small effect on clearance

24. Allegra NDA Database • Acid metabolite (active) of terfenadine • Over 2,353 patients exposed to Allegra • AE profile was as expected given Allegra’s drug class and indications studied

25. Allegra NDA Database

26. Allegra NDA Database • Reporting of somnolence not dose-related • AE profile in Children additionally showed: • headaches, accidental injuries, cough, fever, pain, otitis media and URIs • No significant safety signals in original NDA

27. Allegra Cardiac Safety • In vitro testing (ion channels, isolated myocytes) showed no evidence of repolarization effects • No whole animal effects even at high exposures • No significant cardiac events reported in clinical trials • No clinical ECG interval effects seen, even at doses up to 690 mg BID

28. Allegra Metabolic Considerations • Fexofenadine minimally metabolized • Drug interaction studies showed small increase in AUC • No evidence of important changes in metabolism in special populations

29. NDA summary • All three drugs with acceptable safety in NDAs • Work-up for cardiac effects reassuring • Claritin with some drug-drug interactions, but no apparent clinical consequences

30. POST-MARKETING • Duration of marketing will affect total numbers of reports • Extent of use will affect total number of reports • Heightened sensitivities may affect number of reports

31. POST-MARKETING • Databases first extensively queried up to 4/2000, updated for serious events • Overall, this assessment shows all 3 drugs to have a good post-marketing safety profile, though a few signals seen • No issues found in review that would warrant reconsideration of approval

32. POST-MARKETING - OTC antihistamines • Review of literature, AERS database also performed • OTC antihistamines have acceptable safety profile • CNS and anticholinergic AEs common • Rare cases of seizures, liver failure, serious cardiac adverse events and other rare events have been noted

33. POST-MARKETING – Claritin 4081 Spontaneous AEs for all loratadine products Most commonly reported events were: Drug ineffective Tachycardia Drug interaction Insomnia Headache Sedation Palpitations Dermatitis Dizziness Nervousness

34. POST-MARKETING – Claritin Serious Cardiac events: • 86 cases were reviewed in depth • Patient ages ranged from 2 to 87 years • 38% of reports were for patients less than 50 years old • Large majority of cases occurred in setting of confounding factors

35. POST-MARKETING – Claritin • Some hepatic terms are included in listing of in Claritin labeling • 5 cases of hepatic failure in AERS database • 3 of 5 had confounding factors • 2 of 5 not otherwise explained, without clear causality

36. POST-MARKETING – Zyrtec 3096 Spontaneous AEs in database for cetirizine Most commonly reported events were: Drug ineffective Pruritus Sedation Drug Interaction Thrombocytopenia Asthenia Urticaria Headache Dermatitis Hypersensitivity

37. POST-MARKETING – Zyrtec Thrombocytopenia (low blood platelets): • 1 case in NDA database • 170 cases in the AERS database • All but 11 cases were not plausibly linked to cetirizine use • Review of the 11 cases do not provide a clear link to the drug

38. POST-MARKETING – Zyrtec • Seizures - 64 cases • 26 cases discounted as implausibly linked • 38 cases were reviewed in depth, 5 were not seizure events • Ages ranged from 3 to 79 years • 21 new onset / 12 pre-existing seizure

39. POST-MARKETING – Zyrtec Serious cardiac events • 37 cases were reviewed in depth • Patient ages ranged from 3 to 80 years • More than half under 50 years • Majority of cases with confounding features

40. POST-MARKETING – Allegra 1768 Spontaneous AEs for fexofenadine products Most commonly reported events were: Drug ineffective Sedation Nausea Insomnia Dizziness Palpitations Dermatitis Diarrhoea Headache Dyspnoea

41. POST-MARKETING – Allegra Serious cardiac events • 39 cases reviewed • Age range from 15 to 81 years • Of the most serious cases, the majority had a prior cardiac history and/or concomitant drugs

42. POST-MARKETING – Allegra Seizures • 17 of 30 cases were reviewed in depth • ages ranged from 22 to 80years old • 9 patients with no previous history • 10 patients on drugs known to cause seizures • 8 with dechallenge, 1 possible rechallenge

43. POST-MARKETING • Some signals arise in AERS database • After careful review, each drug has some cases of cardiac events and seizures that cannot be otherwise explained • All these events occur with some background rate in the general population

44. Epidemiology Assessment • The epidemiology staff within OPDRA estimated reporting rates for these 3 drugs vs. expected background incidences • Events examined • serious cardiac events • seizures • hepatotoxicity for loratadine

45. Epidemiology Assessment • Background incidence rates were estimated for comparison purposes • Drug experience comes from a mixed-risk population • “Denominator” for rates inferred from actual use data

46. Epidemiology Assessment • Serious Cardiac Events • estimated incidence of 44 per million person-years • New Onset Solitary Seizures • Estimated incidence of 90 per millionperson-years • Hepatic Failure • Estimated incidence of 1 to 2.3 per million person-years

47. Epidemiology Conclusions: • The calculated reporting rates for all three drugs were comparable for serious cardiac events and seizures • Reporting rates are below background rate for all three drugs and all events • Due to limitations of the data and these analyses, a safety problem for one or more of these drugs cannot be excluded

48. Overall Clinical/Regulatory Conclusions

49. Overall Conclusions • Loratadine, fexofenadine, cetirizine have extensive, favorable marketing histories and safety profiles • FD&C Act sets criteria for when a drug should be Rx-only vs. OTC • The US market has OTC antihistamines available to treat symptoms of allergic rhinitis

50. Overall Conclusions • BC/BS petition requests FDA to initiate a switch of three Rx antihistamines to OTC status • Available data for these drugs supports them being effective for allergic rhinitis • Some low-frequency safety “signals” do arise from the post-marketing experience • Weight of safety evidence is that all three drugs have a favorable safety profile