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Selegiline Transdermal System (STS)

FDA Psychopharmacologic Drugs Advisory Committee. Selegiline Transdermal System (STS). October 26, 2005. Introduction. Melissa Goodhead, BSc, RAC Group Director, Regulatory Affairs / Quality Assurance Somerset Pharmaceuticals. FDA Questions. 1.

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Selegiline Transdermal System (STS)

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

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

  3. FDA Questions 1. • 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? 2.

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

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

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

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

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

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

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

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

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

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

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

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

  16. 100 100 90 90 80 80 70 70 Cortex 60 60 Duodenum 50 50 Percentage inhibition Percentage inhibition Liver 40 40 30 30 20 20 10 10 0.1 1.0 10.0 100 0.4 0.71 1.0 1.5 2.0 2.5 Daily dose (mg/kg) Daily dose (cm2/24 h) Inhibition of MAO by Selegiline in Guinea Pigs Oral Selegiline Transdermal Selegiline Mawhinney et al. J Pharm Pharmacol 2003.

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

  18. Positive Placebo-controlled Efficacy Trialswith Transdermal Selegiline †K-M Relapse = Kaplan Meier time to relapse analysis

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

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

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

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

  23. AERS & IMS Health Records for Oral Selegiline • Pharmacovigilance data (1997-2005) • Rate of hypertensive crisis per 100,000 exposure-years Eldepryl Parnate 1.56 43.36

  24. AERS: 4 Reports of Hypertensive Crisis • 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 • One report: no details available • Must consider tyramine-related • Tyramine-related hypertensive crisis • <0.4 per 100,000 exposure-years

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

  26. DATATOP:Cardiovascular/Cerebrovascular Events

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

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

  29. Tyramine Pressor Test Model • Baselinetyraminechallenge • Active drugtreatment • On-drugtyramine challenge Endpoint: 30 mmHg SBP

  30. Model: Minimum Pressor Dose • Baselinetyraminechallenge • Active drugtreatment • On-drugtyramine challenge • Example • Minimum • Pressor • dose 200 mg • Minimum • Pressor • dose 400 mg

  31. Model: Tyramine Sensitivity Factor (TSF) • Baselinetyraminechallenge • Active drugtreatment • On-drugtyramine challenge • Example: Drug 1 • Minimum • Pressor • dose 200 mg • Minimum • Pressor • dose 400 mg • 400/200 = TSF of 2

  32. Model: Tyramine Sensitivity Factor (TSF) • Baselinetyraminechallenge • Active drugtreatment • On-drugtyramine challenge • Example: Drug 2 • Minimum • Pressor • dose 10 mg • Minimum • Pressor • dose 400 mg • 400/10 = TSF of 40

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

  34. 338 ± 112 (271, 406) 385 ± 128 (307, 462) TSF: Transdermal 20 mg vs. Oral Selegiline 10 mg Mean Pressor Dose(mg Tyramine) 338 385 1.75 ± 0.54 1.67 ± 1.04 Tyramine Sensitivity Factor TransdermalSelegiline20 mg Oral Selegiline10 mg Crossover data 1.75 ± 0.54 (1.43, 2.07) 1.67 ± 1.04 (1.04, 2.30)

  35. 338 ± 112 (271, 406) 385 ± 128 (307, 462) 408 ± 131 (325, 492) TSF of Fluoxetine 60 mg Mean Pressor Dose(mg Tyramine) 338 385 408 1.75 ± 0.54 1.67 ± 1.04 1.43 ± 0.56 Tyramine Sensitivity Factor TransdermalSelegiline20 mg Oral Selegiline10 mg Fluoxetine 60 mg 1.75 ± 0.54 (1.43, 2.07) 1.67 ± 1.04 (1.04, 2.30) 1.43 ± 0.56 (1.08, 1.79)

  36. 10 ± 0(10, 10) 270 ± 82 (211, 329) TSF of Tranylcypromine 30 mg (Parnate) Mean Pressor Dose(mg Tyramine) 270 10 40.00 ± 7.07 Tyramine Sensitivity Factor 1.86 ± 0.42 TransdermalSelegiline20 mg Tranylcypromine30 mg Crossover data 1.86 ± 0.42 (1.57, 2.16) 40.00 ± 7.07 (34.56, 45.44)

  37. 40 mg Day 30 Transdermal Selegiline40 mg Day 60 40 mg Day 90 TSF Stability Over Time (40 mg dose) Mean Pressor Dose(mg Tyramine) 84 66 88 10 Tyramine Sensitivity Factor Tranylcypromine30 mg/d Day 8 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)

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

  39. 64 ± 27 (47.05, 127.9) 172 ± 92 (94.93, 248.8) Pressor Dosemean ± SD (95% CI) Pharmacodynamic Effect of Food onPressor Dose 64 172 Mean Pressor Dose p = 0.0023 Pressor Dose(mg Tyramine) Transdermal Selegiline40 mg Fasting Transdermal Selegiline40 mg Fed

  40. Tyramine Content in a High-Tyramine Meal

  41. Pressor Dose Range at Steady State Mean Pressor Dose(mg Tyramine) 256 204 10 Tyramine Sensitivity Factor Transdermal Selegiline 20 mg 21 Days TransdermalSelegiline 20 mg 30 Days Tranylcypromine30 mg

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

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

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

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

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

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

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

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

  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?

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