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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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FDA Psychopharmacologic Drugs Advisory Committee

Selegiline Transdermal System (STS)

October 26, 2005


Introduction

Melissa Goodhead, BSc, RAC

Group Director, Regulatory Affairs / Quality AssuranceSomerset Pharmaceuticals


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.


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


Overview

Sheldon Preskorn, MD

Chairman, Department of PsychiatryUniversity of Kansas, Wichita

5


Overview

  • Clinical Depression

  • Characteristics of MAOI

  • Oral MAOI and tyramine

  • Medical need for MAOI without dietary modifications

  • Transdermal delivery of MAOI


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


Characteristics of Monoamine Oxidase Inhibitors

  • First antidepressants

  • Established efficacy

  • Affect three neurotransmitters

  • Infrequently used despite their efficacy in part because of dietary restrictions


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


MAO in the Gut

  • Barrier preventing systemic absorption of tyramine

  • Virtually impossible to eat enough tyramine in food to overcome this barrier


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


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


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


The Clinical Need

  • The efficacy of the oral MAOIs without the need for a tyramine-restrictive diet


Oral versus Transdermal Delivery

Oral MAOI

Transdermal Selegiline

20 mg patch

skin


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.


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

17


Positive Placebo-controlled Efficacy Trialswith Transdermal Selegiline

†K-M Relapse = Kaplan Meier time to relapse analysis


Safety – Tyramine

Lawrence Blob, MD

Medical Director, Somerset Pharmaceuticals


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


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


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


AERS & IMS Health Records for Oral Selegiline

  • Pharmacovigilance data (1997-2005)

  • Rate of hypertensive crisis per 100,000 exposure-years

    EldeprylParnate

    1.5643.36


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


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%)


DATATOP:Cardiovascular/Cerebrovascular Events


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


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)


Tyramine Pressor Test Model

  • Baselinetyraminechallenge

  • Active drugtreatment

  • On-drugtyramine challenge

Endpoint: 30 mmHg SBP


Model: Minimum Pressor Dose

  • Baselinetyraminechallenge

  • Active drugtreatment

  • On-drugtyramine challenge

  • Example

  • Minimum

  • Pressor

  • dose 200 mg

  • Minimum

  • Pressor

  • dose 400 mg


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


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


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)


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)


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)


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)


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)


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


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


Tyramine Content in a High-Tyramine Meal


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


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


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


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


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


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


Analysis of Blood Pressure Increases in Placebo-Controlled Trials

  • N = 1430 subjects in controlled trials

  • ↑ 20 mmHg over baseline SBP and SBP >160

    Transdermal SelegilinePlacebo

    1.4% 1.9%

  • Incidence of AE Hypertension

    Transdermal SelegilinePlacebo

    0.6% 0.7%


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


Provider / Patient Awareness

Chad VanDenBerg, Pharm.D., BCPP

Director, Clinical Affairs & Product Information

Somerset Pharmaceuticals, Inc.

49


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?


Education Plan

  • Goal: 100% awareness of the need for dietarymodifications at the higher strengths(30 and 40 mg patches)

  • Major elements

    • Multiple education and outreach tools

      • Prescribers

      • Pharmacists

      • Patients

    • Uniquely designed packaging


Objective and Considerations

  • Primary Objective

    • Dietary modification instructions

  • Implementation Considerations

    • Prevent simultaneous use of multiple patches

    • Appropriate titration instructions


Study of Physician and Patient Comprehension of the Need for Dietary Modifications

  • Methodology

    • 75 Physicians

      • Psychiatrists and primary care physicians

    • 70 Patients

  • Results after only one exposure

    • 96% of physicians and 94% of patients correctly identify the need for dietary modifications at higher doses

  • Plan calls for multiple exposures


Prescriber Education

  • Key Elements

    • Instructions for appropriate product usage consistent with label

    • Patient education materials

    • Verbally communicate

      • Use as prescribed

      • Apply one patch at a time

      • Stay on modified diet for two weeks after discontinuation

    • Write dietary modificationsrequired on prescriptions

  • Continual Monitoring

    • Bi-weekly assessment of awareness and practices


Pharmacist Education

  • Key Elements

    • Educational programs including teleconferences and mailings

    • Up-to-date product information available through 3rd party data sources


Patient Education

  • Patient education materials

  • Patient information leaflet

  • Patient starter pack

  • EMSAM website


Dietary Modifications Required

57


Pharmacovigilance Program

  • Education and outreach program

  • Pharmacovigilance procedures and reporting

  • Targeted follow up on specific adverse events

    • Hypertensive crisis and other CV events


Provider / Patient Awareness Summary

  • Multi-faceted plan

    • Enhanced education program

      • Prescribers

      • Pharmacists

      • Patients

    • Distinctive packaging

    • Enhanced pharmacovigilance


Conclusions

Melvin Sharoky, MD

CEO and President

Somerset Pharmaceuticals, Inc.

60


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