CLARITIN ® (10 mg loratadine) OTC Indication for Chronic Idiopathic Urticaria

1. CLARITIN®(10 mg loratadine)OTC Indication for Chronic Idiopathic Urticaria Schering Corporation April 22, 2002

2. Background Joint Non-Prescription Drug and Pulmonary-Allergy Advisory Committees review on May 11, 2001: Loratadine (10 mg daily) is safe for OTC treatment of allergic rhinitis

3. Objective To consider loratadine for treating episodes of chronic idiopathic urticaria (CIU) OTC following an initial physician diagnosis

4. Agenda Overview John M. Clayton, Ph.D. Clinical Overview of Urticaria Eugene W. Monroe, M.D. Schering Studies on CIU Stephen Neumann Risk/Benefit Analysis and Conclusions John M. Clayton, Ph.D.

5. CIU as an OTC Indication • In-depth Review of CIU Indication • New Studies • CIU Patient Study • Physician Practices • Consumer Self-Recognition • Label Comprehension • Claritin® Worldwide Safety Review • Expert Panel Review

6. Findings • CIU is generally not associated or confused with more serious conditions • CIU is currently managed by consumers as a self-treated condition • Physicians and consumers are comfortable with consumers’ ability to self-recognize recurring episodes of CIU

7. Findings • Consumers already self-treat with OTC sedating antihistamines • Claritin® is safe for OTC treatment of CIU and provides a better risk/benefit alternative • Adequate labeling can be developed for Claritin® OTC for safe and effective OTC use in CIU following an initial physician diagnosis

8. URTICARIA (Hives) Eugene W. Monroe, M.D. Department of Dermatology, Advanced Healthcare Assistant Clinical Professor, Medical College of Wisconsin

9. Objectives of Presentation • Overview of Urticaria (Hives) • Classification • Diagnostic Evaluation • Management • Consequences of (consumer/patient) misdiagnosis?

10. Urticaria (Hives): • Skin reaction pattern characterized by transient, pruritic, edematous, • lightly erythematous papules or wheals, frequently with central clearing

11. Differentiating Acute from Chronic Urticaria (Hives) • Acute Urticaria (Hives) • Duration of few days to few weeks • Incidence of 15-20% of population • Etiology usually detected • Most cases are mild and never seen by physician • Chronic Urticaria (Hives) • Duration greater than six weeks • Ranges from continuous (almost daily) to recurrent (symptom free intervals of days to many weeks) • Course variable from months to years • Incidence of up to 3% of population • Etiology not found in 90-95% of cases = IDIOPATHIC (cause unknown or not determined)

12. Drugs Foods Infections Psychogenic Factors Physical Agents Inhalants Contactants Genetic Factors Internal Diseases (Connective Tissue Disorders, Vasculitis, Thyroid, etc.) Potential Causes of Urticaria (Hives) Most Common Causes Other Causes

13. Diagnosing Chronic Idiopathic Urticaria (Chronic Hives of Unknown Cause) • History & Physical Examination • Detailed history is most important diagnostic test • Review of systems • Review of the potential causes for hives • Physical exam • Laboratory and diagnostic tests only ordered based on clues from history and physical exam • CIU - a Diagnosis of Exclusion

14. Management of Acute Urticaria (Hives) • Elimination or reduction of underlying cause • Patient Education • Natural course of disease and etiologies • Possible complications and associated conditions and appropriate actions • Drug Therapy • H1 antihistamine

15. Management of Chronic Idiopathic Urticaria • Reduction or avoidance of non-specific aggravating factors • Patient Education • Natural course of disease and etiologies • Possible complications and appropriate actions • Drug therapy

16. Treatment Algorithm for Chronic Idiopathic Urticaria • H1 antihistamines - (Non-sedating preferred) • H1 antihistamine + other H1 & H2 receptor blockers, inhibitors of other mediators, or inhibitors of the inflammatory and cellular reaction • Additional medications are used when the symptoms persist and efficacy is not optimal with monotherapy

17. Spectrum of Urticaria Patients • Range of Urticaria (hive) patients: • a milder (self-limiting) form to very severe (refractory) • Range of consumer/patient participation with the physician: • not seeing physician & self treating to active participation • Treatment of Urticaria Patients • standard of care H1 antihistamines

18. Most Likely Conditions Confused or Misdiagnosed for CIU • Acute/Chronic Urticaria (Hives) • Eczema/Contact Dermatitis • Angioedema

19. Consequences of Misdiagnosis Acute Urticaria (Hives) • Vast majority of cases mild & self-limiting • An appropriate treatment for acute hives is an antihistamine

20. Consequences of Misdiagnosis Chronic Urticaria • 5-10% have an identifiable cause • Patients will usually be driven to the physician due to: • severity/persistence of itching • failure to respond to self-treatment • presence of other signs and symptoms suggestive of a more serious condition (joint pain, fever, discoloration of the hives etc.)

21. Consequences of Misdiagnosis Dermatitis/Eczema • Most likely confusion with other “itchy rashes”(e.g. Contact Dermatitis, Eczema) • Patients will usually seek a physician when: • changing severity/persistence of symptoms • failure to respond to self-treatment

22. Consequences of Misdiagnosis Angioedema • Angioedema & urticaria can co-exist and can sometimes be confused with each other • Angioedema are giant hives or hives involving mucous membranes and tissues around the eyes, lips or genitalia • Histologically involves deeper layers of skin than urticaria • Although visually more noticeable than urticaria, present no additional serious consequences to the patient • No difference with clinical treatment

23. Anaphylaxis • An immediate systemic allergic reaction produced by the release of mediators from mast cells and basophils • Simultaneously involves • Skin manifestations (hives) • Respiratory systems- (dyspnea, wheeze) • CV system (dizziness, syncope, hypotension) • GI system (nausea, vomiting, diarrhea) • Incidence of anaphylaxis is rare1,2 1. Yocum, Rochester Epidemologic Study - Journ Allergy Clin Immuno 104:452-6, 1999 2. Neugut, Arch. Int. Med. Vol.161, Jan 8, 2001

24. Anaphylaxis (cont.) • Chronic urticaria is not associated with nor is it a risk factor for the development of anaphylaxis 3 • Acute urticaria is an associated symptom with anaphylaxis but the rapid simultaneous onset of CV or Respiratory symptoms will cause the patient to seek immediate medical attention • Respiratory and Cardiovascular symptoms most always occur within 30 minutes of presentation of the hives 3. Winbery, Lieberman, Immun Clinic North America Vol 15 no 3 Aug ‘95

25. Conclusions • Cardinal features of urticaria (acute or chronic) • cutaneous wheals, redness and itching • Diagnosis of Chronic Idiopathic Urticaria • a diagnosis of exclusion by physicians • Consequences of patient misdiagnosis represents a low safety risk • Availability of OTC non-sedating H1 antihistamines in CIU: • Better safety profile (vs.current OTC antihistamines) • Creates opportunity for better care through labeling and patient education

26. Chronic Idiopathic Urticaria:Key Studies Conducted BySchering-Plough

27. Study Purpose Consumer Habits and Practices Study (N=388) Understand how patients with CIU recognize and treat their symptoms Physician Practices Study (N= 359) Understand physician practices and perceptions regarding CIU among a representative sample of key specialties Consumer Self-Recognition Study (N=196) Label Comprehension Study (N=565) Learn how well CIU patients self-recognize CIU and its symptoms and self-manage after initial physician diagnosis Schering Conducted Four Studies Understand consumer’s ability to comprehend certain communications points on the draft label

28. Consumer Study Design Screening of Subjects • Internet panel screened via e-mail questionnaire to identify physician-diagnosed CIU sufferers • Question Posed • “Have you ever been diagnosed by a medical doctor as having chronic or recurrent hives that have no known discernable cause, also known as chronic idiopathic urticaria?” Re-screening/Validation of Subjects • Random sample drawn from CIU sampling frame and asked to log on to a website to complete a more detailed questionnaire • Subjects were re-screened for physician diagnosed CIU at log in • Literature on consumer research supports that most respondents provide accurate responses to study questions on personal health issues such as conditions personally suffered (excluding sensitive topics such as STD’s)

29. Consumer Study Population US Adult (18+) Population Age: 18-24 4% 13% 25-29 7 9 30-39 21 21 40-49 29 21 50-59 27 14 60-69 9 10 70+ 3 12 Sex: Male 34 48 Female 66 52 Consumer Study Design Study Population • Final sample (N=388) is representative of larger pool of CIU responders and has a profile consistent with key demographics reported with CIU • Female; Middle aged

30. Consumer Study Design • Survey questions comprised primarily of a variation of closed-ended or multiple choice type questions • Subjects could type in responses whenever pre-set lists did not meet their needs • All key questions had this option • Possible response lists were rotated to minimize order bias in presentation • Closed ended questions are a standard, accepted practice in survey research and offer a number of advantages • Are a good choice when the options are limited and can be foreseen • Permit direct comparison of responses from subject to subject • Address the issue that most respondents will not write elaborate answers • Avoid interviewer recording/probing biases present in open-ends • Avoid errors associated with coding/ categorization of responses

31. Q. In a typical year, how many episodes of chronic hives do you experience?

32. (N=388) Frequency of Suffering 42% 3 or More Episodes/Year 66% 34% 24% Mean = 3.4 times • CIU sufferers are experienced, frequent sufferers making it a readily recognizable condition

33. Q. Please indicate the symptoms you experience when your hives recur.

34. Symptoms of CIU Note: Responses do not equal 100 due to multiple responses (N=388) • There is significant consistency in symptoms described by CIU sufferers • Symptoms that could be confused with the most threatening manifestations • of anaphylaxis are rarely mentioned

35. Q. Thinking about when the hives appeared prior to seeing a physician, what, if anything, did you do to treat or relieve the condition? (Question context is prior to diagnosis of CIU)

36. Action at Initial Occurrence Total (N=388)Used any OTC- topical or systemic (Net) 70 % Took an OTC antihistamine such as Benadryl or Chlor-Trimeton62 % Used a topical anti-itch cream such as Benadryl 36 % Used a topical anti-itch lotion such ascalamine lotion 46 % Note: Multiple Mentions • Self-medication prior to physician diagnosis is a common behavior and OTC • oral antihistamines are commonly used

37. Q. In the past year, how often have you seen a physician for this condition?

38. Physician Care • One-third (33%) of study subjects have not seen a physician for CIU in the past year • Nearly one-fifth (19%) report that they have not seen a physician since initial diagnosis • A notable proportion of patients are not under continual care

39. Q. When your chronic hives recur, please indicate what you normally do?

40. Typical Action Upon Recurrence (N=388) Use prescribed medication already on hand 52% Use OTC medication 43 Call/visit physician 20 Take bath/soothing bath/soak wash areas 3 Nothing/wait it out/no longer have problem 8 Go to emergency room 1 All other mentions 5 Note: Multiple Mentions • Patients self-manage CIU with the use of both prescription • medications on hand and OTC medications

41. (N=388) Subjects Who Call/Visit Physician 20 % When Contact Physician Every time 4 % Sometimes 4 % Only when symptoms don’t respond to current treatments/medication(s) 7 % Only when a more serious symptom such as swelling of face/mouth occurs 2 % No answer 3 % Physician Contact • Most physician contact comes about when symptoms don’t • respond or more serious symptoms occur

42. Q. Now that your condition has been diagnosed by a physician, how easy is it for you to identify this condition when it reappears?

43. Ability to Self-Recognize CIU (N=388) Ease of Recognition Very easy 80 % Somewhat easy 14 % Very/Somewhat Easy94 % Neither easy nor difficult 6 % Somewhat difficult - Very difficult - • Once diagnosed by a physician as having CIU • 80% of patients perceive it is very easy to identify the • condition when it reappears • - No respondents reported difficulty

44. Q. What would you do if you experienced other symptoms such as difficulty breathing, fever or trouble swallowing with your hives?

45. 95% Presence of Serious Symptoms (N=388) * Less than 1% • 95% of patients claim that they would seek medical assistance • if more serious symptoms arose • This response is without the benefit of labeling to direct them

46. Conclusions: Consumer Study • Consumers confirm that recurrent episodes of CIU are easily recognized • Physician diagnosed CIU is largely self-managed • Nearly 20% do not return for a physician visit • Treatment with OTC antihistamines prior to physician diagnosis is prevalent (62%) • Consumers know to seek medical attention if serious symptoms occur

47. Physician Practices Study Design Physician Screening • Internet panel of physicians combined with a pool of physicians from Medscape and ePocrates totaling 200,000 • Pool of physicians screened as to specialty and treatment of CIU patient • Once qualified, more detailed survey conducted

48. Physician Practices Study Design Study Population • Random sample drawn was representative of and projectable to office-based practicing physicians with web access (96%) in the specialties studied • Total of 359 interviews • PCP’s , Dermatologists, Allergists, Pediatricians

49. Q. What terminology do you typically usewhen explaining the initial diagnosis to your patients?

50. Nomenclature Used To Describe CIU (N=359) • Nearly three-fourths of physicians use either “chronic” or “recurring” • hives in describing CIU to their patients