1. 1 Selegiline Transdermal System (STS) FDA Psychopharmacologic Drugs Advisory Committee October 26, 2005

2. 2 Introduction Melissa Goodhead, BSc, RAC Group Director, Regulatory Affairs / Quality Assurance Somerset Pharmaceuticals

3. 3 FDA Questions Do the available data for the EMSAM 20 mg patch support the reasonable safety of this formulation without the need for dietary restrictions? If the EMSAM 20 mg patch formulation could be considered reasonably safe for marketing without the need for dietary restrictions, would it be acceptable to market the 20 mg patch without dietary restrictions and at the same time require dietary restrictions for the 30 and 40 mg patch strengths? 1. 2.

4. 4 Selegiline – Presentation Agenda Overview................ Safety – Tyramine......... Physician & Patient Awareness Program....... Conclusion – Q&A......... Sheldon Preskorn, MD Lawrence F. Blob, MD Chad VanDenBerg, PharmD Melvin Sharoky, MD

5. 5 Overview Sheldon Preskorn, MD Chairman, Department of Psychiatry University of Kansas, Wichita 5

6. 6 Overview u Clinical Depression u Characteristics of MAOI u Oral MAOI and tyramine u Medical need for MAOI without dietary modifications u Transdermal delivery of MAOI

7. 7 Facts About Clinical Depression u High prevalence u Significant morbidity and mortality u Heterogeneous illness: No single antidepressant works for every patient u 30% do not respond to a series of different antidepressants u Need for additional effective options

8. 8 Characteristics of Monoamine Oxidase Inhibitors u First antidepressants u Established efficacy u Affect three neurotransmitters u Infrequently used despite their efficacy in part because of dietary restrictions

9. 9 Infrequent MAOI Use u IMS 2005 – 0.1% of all antidepressant prescriptions u APA guidelines 2000 cite dietary restrictions as a reason to limit use u Surveys have shown dietary restrictions as a major deterrent to MAOI usage

10. 10 MAO in the Gut u Barrier preventing systemic absorption of tyramine u Virtually impossible to eat enough tyramine in food to overcome this barrier

11. 11 Oral MAOIs and Dietary Tyramine u Oral MAOIs substantially inhibit intestinal MAO u Tyramine can enter systemic circulation u Systemic tyramine causes release of NE u Large dose of tyramine can cause dramatic rise in blood pressure via NE

12. 12 Hypertensive Crisis u Not chronic or essential hypertension u Medical emergency requiring immediate treatment u Acute elevation in BP >180/120 mmHg leading to end-organ damage u Tyramine-induced hypertensive crisis –onset between 10 minutes and 2 hours after meal

13. 13 Current MAOI Diet Recommendations u Avoid high tyramine foods –Aged cheeses –Fermented or spoiled meats –Some yeast extracts (e.g., marmite) u Maximum tyramine content meal: 40 mg tyramine u The need for the diet and the potential risk of hypertensive crisis discourages MAOI use

14. 14 The Clinical Need The efficacy of the oral MAOIs without the need for a tyramine-restrictive diet

15. 15 Oral versus Transdermal Delivery 20 mg patch skin Oral MAOITransdermal Selegiline

16. 16 Mawhinney et al. J Pharm Pharmacol 2003. Inhibition of MAO by Selegiline in Guinea Pigs Cortex Oral Selegiline Transdermal Selegiline DuodenumLiver Percentage inhibition Daily dose (mg/kg) 0.11.010.0100 10 20 30 40 50 60 70 80 90100 Daily dose (cm 2 /24 h) 10 20 30 40 50 60 70 80 90100 Percentage inhibition 0.40.711.01.52.02.5

17. Can the 20 mg transdermal delivery system for selegiline provide antidepressant efficacy without the need for dietary modification? 17

18. 18 Positive Placebo-controlled Efficacy Trials with Transdermal Selegiline E106P0052P9806 Duration 6 weeks 8 weeks 52 weeks N176265322 EMSAM Dose 20 mg 20 mg 20, 30, or 40 mg 20, 30, or 40 mg 20 mg 20 mg Primary Endpoint HAMD-17 p = 0.018 HAMD-28 p = 0.033 K-M Relapse † p = 0.006 † † K-M Relapse = Kaplan Meier time to relapse analysis

19. 19 Safety – Tyramine Lawrence Blob, MD Medical Director, Somerset Pharmaceuticals

20. 20 Safety of Transdermal Selegiline u Oral selegiline: 16 years of safe use with normal diet u Tyramine challenge program shows oral and transdermal selegiline have equally low intestinal MAO inhibition u Food challenges demonstrate tyramine safety of 20 mg transdermal selegiline u Phase III safety data found no hypertensive crises in 2,503 MDD patients at 20, 30, and 40 mg

21. 21 10 mg Oral and 20 mg Transdermal Selegiline u Same active ingredient u Unlike oral, transdermal selegiline achieves antidepressant levels in CNS u Like oral, transdermal maintains the intestinal barrier to tyramine

22. 22 Safety of Oral Selegiline (Eldepryl) u 16 years of safe use in Parkinson’s disease –Approved in 1989 –No dietary modifications –1.5 million patients exposed

23. 23 AERS & IMS Health Records for Oral Selegiline u Pharmacovigilance data (1997-2005) u Rate of hypertensive crisis per 100,000 exposure-years EldeprylParnate 1.5643.36

24. 24 AERS: 4 Reports of Hypertensive Crisis u 3 determined not related to tyramine –Case 1: tolcapone, levodopa, carbidopa, bromocriptine, ropinirole –Case 2: ephedrine, theophylline, levodopa, carbidopa, lisuride, maprotiline –Case 3: levodopa, bromocriptine, talipexole u One report: no details available –Must consider tyramine-related u Tyramine-related hypertensive crisis –<0.4 per 100,000 exposure-years

25. 25 DATATOP: Controlled Safety Data u Study of oral selegiline and Vitamin E for the treatment of Parkinsonism u N = 800 u 2,970 patient-years of exposure u No increase in mortality (2.1%) compared to a matched population (2.7%)

26. 26 DATATOP: Cardiovascular/Cerebrovascular Events Incidence per 1000 patient-years Oral Selegiline Placebo MI6.48.1 CVA / TIA 6.713.0

27. 27 Safety of Transdermal Selegiline u Oral selegiline: 16 years of safe use with normal diet u Tyramine challenge program shows oral and transdermal selegiline have equally low intestinal MAO inhibition u Food challenges demonstrate tyramine safety of 20 mg transdermal selegiline u Phase III safety data found no hypertensive crises in 2,503 MDD patients at 20, 30, and 40 mg

28. 28 Tyramine Challenge Studies 14 tyramine challenge studies (N=214) u Time of exposure, up to 96 days u Dose (20 to 40 mg transdermal selegiline) u Fasting versus fed conditions u Comparator drugs –Oral selegiline (Eldepryl) –Fluoxetine (Prozac) –Tranylcypromine (Parnate)

29. 29 Tyramine Pressor Test Model Endpoint: 30 mmHg SBP Baseline tyramine challenge Active drug treatment On-drug tyramine challenge

30. 30 Model: Minimum Pressor Dose Example MinimumPressor dose 200 mg MinimumPressor dose 400 mg Minimum Pressor Dose: Smallest oral tyramine dose to cause 30 mmHg SBP Baseline tyramine challenge Active drug treatment On-drug tyramine challenge

31. 31 Model: Tyramine Sensitivity Factor (TSF) Example: Drug 1 400/200 = TSF of 2 MinimumPressor dose 200 mg MinimumPressor dose 400 mg Baseline tyramine challenge Active drug treatment On-drug tyramine challenge

32. 32 Model: Tyramine Sensitivity Factor (TSF) Example: Drug 2 MinimumPressor dose 10 mg MinimumPressor dose 400 mg 400/10 = TSF of 40 Baseline tyramine challenge Active drug treatment On-drug tyramine challenge

33. 33 Comparator Studies u Crossover studies –Transdermal selegiline 20 mg vs. oral selegiline 10 mg (Eldepryl) –Transdermal selegiline 20 mg vs. tranylcypromine 30 mg (Parnate) u Negative control –Fluoxetine 60 mg (Prozac)

34. 34 TSF: Transdermal 20 mg vs. Oral Selegiline 10 mg Mean Pressor Dose (mg Tyramine) 338385 1.75 ± 0.541.67 ± 1.04 Transdermal Selegiline 20 mg Oral Selegiline 10 mg 338 ± 112 (271, 406) 385 ± 128 (307, 462) 1.75 ± 0.54 (1.43, 2.07) 1.67 ± 1.04 (1.04, 2.30) Tyramine Sensitivity Factor Crossover data

35. 35 Tyramine Sensitivity Factor 338385 Fluoxetine 60 mg 408 1.43 ± 0.561.75 ± 0.541.67 ± 1.04 TSF of Fluoxetine 60 mg Transdermal Selegiline 20 mg Oral Selegiline 10 mg 408 ± 131 (325, 492) 1.43 ± 0.56 (1.08, 1.79) 338 ± 112 (271, 406) 385 ± 128 (307, 462) 1.75 ± 0.54 (1.43, 2.07) 1.67 ± 1.04 (1.04, 2.30) Mean Pressor Dose (mg Tyramine)

36. 36 27010 TSF of Tranylcypromine 30 mg (Parnate) Transdermal Selegiline 20 mg Tranylcypromine 30 mg 40.00 ± 7.07 1.86 ± 0.42 10 ± 0 (10, 10) 40.00 ± 7.07 (34.56, 45.44) 270 ± 82 (211, 329) 1.86 ± 0.42 (1.57, 2.16) Mean Pressor Dose (mg Tyramine) Tyramine Sensitivity Factor Crossover data

37. 37 TSF Stability Over Time (40 mg dose) Tyramine Sensitivity Factor 84668810 11.45 ± 6.59 (8.17, 14.73) 11.36 ± 5.13 (8.40, 14.33) 9.33 ± 5.20 (5.84, 12.82) 40.00 ± 7.07 (34.56, 45.44) Tranylcypromine 30 mg/d Day 8 Transdermal Selegiline 40 mg Day 60 40 mg Day 90 40 mg Day 30 Mean Pressor Dose (mg Tyramine)

38. 38 Safety of Transdermal Selegiline u Oral selegiline: 16 years of safe use with normal diet u Tyramine challenge program shows oral and transdermal selegiline have equally low intestinal MAO inhibition u Food challenges demonstrate tyramine safety of 20 mg transdermal selegiline u Phase III safety data found no hypertensive crises in 2,503 MDD patients at 20, 30, and 40 mg

39. 39 64 ± 27 (47.05, 127.9) 172 ± 92 (94.93, 248.8) Pharmacodynamic Effect of Food on Pressor Dose Pressor Dose (mg Tyramine) Pressor Dose mean ± SD (95% CI) Transdermal Selegiline 40 mg Fasting Fed 64172 Mean Pressor Dose p = 0.0023

40. 40 Tyramine Content in a High-Tyramine Meal Sample Meal Portion (g or mL) Tyramine content (mg/portion) Bottled beer Sauerkraut Boiled potatoes Green and yellow peppers Roast Pork Pepper sauce Cheese Camembert Camembert Danish blue Danish blue Pinot Noir 70045445425045415030307001.016.71.91.83.23.01.48.82.0 Total tyramine in meal 39.8

41. 41 Transdermal Selegiline Transdermal Selegiline 20 mg 21 Days Tranylcypromine 30 mg 10 Tyramine Sensitivity Factor Mean Pressor Dose (mg Tyramine) Transdermal Selegiline Transdermal Selegiline 20 mg 30 Days 204256 Pressor Dose Range at Steady State

42. 42 Safety Margin: 20 mg Transdermal, Extremes (Calculated for Fed Conditions) 20 mg N = 2 N = 10 Minimum = 125 mg Minimum = 25 mg 40 mg Tyramine (mg) < 5 mg Tyramine Typical Meal

43. 43 Tyramine Challenge Program Conclusions u 20 mg transdermal and oral selegiline and fluoxetine all have similar TSF, about 14-20 times less than that of tranylcypromine u 40 mg transdermal selegiline has a TSF 4 times less than tranylcypromine u Patients taking 20 mg transdermal selegiline will be unable to eat enough tyramine-rich food to cause a hypertensive crisis

44. 44 Safety of Transdermal Selegiline u Oral selegiline: 16 years of safe use with normal diet u Tyramine challenge program shows oral and transdermal selegiline have equally low intestinal MAO inhibition u Food challenges demonstrate tyramine safety of 20 mg transdermal selegiline u Phase III safety data found no hypertensive crises in 2,503 MDD patients at 20, 30, and 40 mg

45. 45 Phase III Safety u Exposure in 2500 patients –20, 30, 40 mg transdermal selegiline –No dietary modification u No serious adverse events of hypertensive crisis u No deaths

46. 46 Events of Interest Review Process Step I: Comprehensive Computer Term Search u COSTART terms: Amblyopia, arrhythmia, bradycardia, chest pain, coma, headache (severe), hypertension, migraine, neck rigidity, palpitation, stupor, tachycardia u Blood Pressure: Occurrence of blood pressure  160/100 mmHg anytime during the study Step II: Algorithm u Any patient with AE term hypertension, migraine or severe headache u Any AE terms judged at least moderate in intensity u Any AE requiring treatment u Occurrence of blood pressure  160/100 mmHg anytime during the study Results: No events of hypertensive crisis

47. 47 Analysis of Blood Pressure Increases in Placebo-Controlled Trials u N = 1430 subjects in controlled trials u ↑ 20 mmHg over baseline SBP and SBP >160 Transdermal SelegilinePlacebo Transdermal SelegilinePlacebo 1.4% 1.9% u Incidence of AE Hypertension Transdermal SelegilinePlacebo Transdermal SelegilinePlacebo 0.6% 0.7%

48. 48 Safety Conclusions u 20 mg transdermal selegiline is effective and safe without dietary modifications u 20 mg transdermal selegiline shows a low inhibition of intestinal MAO –Equivalent to 10 mg oral selegiline and 60 mg fluoxetine u No hypertensive crisis in Phase III program u Education program will instruct physicians and patients on proper use of drug

49. 49 Provider / Patient Awareness Chad VanDenBerg, Pharm.D., BCPP Director, Clinical Affairs & Product Information Somerset Pharmaceuticals, Inc. 49

50. 50 FDA Question #2 If the EMSAM 20 mg patch formulation could be considered reasonably safe for marketing without the need for dietary restrictions, would it be acceptable to market the 20 mg patch without dietary restrictions and at the same time require dietary restrictions for the 30 and 40 mg patch strengths?

51. 51 Education Plan Goal: 100% awareness of the need for dietary modifications at the higher strengths (30 and 40 mg patches) Major elements u Multiple education and outreach tools –Prescribers –Pharmacists –Patients u Uniquely designed packaging

52. 52 Objective and Considerations u Primary Objective –Dietary modification instructions u Implementation Considerations –Prevent simultaneous use of multiple patches –Appropriate titration instructions

53. 53 Study of Physician and Patient Comprehension of the Need for Dietary Modifications Methodology u 75 Physicians –Psychiatrists and primary care physicians u 70 Patients Results after only one exposure u 96% of physicians and 94% of patients correctly identify the need for dietary modifications at higher doses Plan calls for multiple exposures

54. 54 Prescriber Education Key Elements u Instructions for appropriate product usage consistent with label u Patient education materials u Verbally communicate –Use as prescribed –Apply one patch at a time –Stay on modified diet for two weeks after discontinuation u Write dietary modifications required on prescriptions Continual Monitoring u Bi-weekly assessment of awareness and practices

55. 55 Pharmacist Education Key Elements u Educational programs including teleconferences and mailings u Up-to-date product information available through 3rd party data sources

56. 56 Patient Education u Patient education materials u Patient information leaflet u Patient starter pack u EMSAM website

57. Dietary Modifications Required 57

58. 58 Pharmacovigilance Program u Education and outreach program u Pharmacovigilance procedures and reporting u Targeted follow up on specific adverse events –Hypertensive crisis and other CV events

59. 59 Provider / Patient Awareness Summary Multi-faceted plan u Enhanced education program –Prescribers –Pharmacists –Patients u Distinctive packaging u Enhanced pharmacovigilance

60. 60 Conclusions Melvin Sharoky, MD CEO and President Somerset Pharmaceuticals, Inc. 60