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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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Slide1 l.jpg

FDA Psychopharmacologic Drugs Advisory Committee

Selegiline Transdermal System (STS)

October 26, 2005


Introduction l.jpg

Introduction

Melissa Goodhead, BSc, RAC

Group Director, Regulatory Affairs / Quality AssuranceSomerset Pharmaceuticals


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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.


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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 l.jpg

Overview

Sheldon Preskorn, MD

Chairman, Department of PsychiatryUniversity of Kansas, Wichita

5


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Overview

  • Clinical Depression

  • Characteristics of MAOI

  • Oral MAOI and tyramine

  • Medical need for MAOI without dietary modifications

  • Transdermal delivery of MAOI


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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 l.jpg
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 l.jpg
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


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MAO in the Gut

  • Barrier preventing systemic absorption of tyramine

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


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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


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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


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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


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The Clinical Need

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


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Oral versus Transdermal Delivery

Oral MAOI

Transdermal Selegiline

20 mg patch

skin


Inhibition of mao by selegiline in guinea pigs l.jpg

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.


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17


Positive placebo controlled efficacy trials with transdermal selegiline l.jpg
Positive Placebo-controlled Efficacy Trials provide antidepressant efficacy without the need for dietary modification?with Transdermal Selegiline

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


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Safety – Tyramine provide antidepressant efficacy without the need for dietary modification?

Lawrence Blob, MD

Medical Director, Somerset Pharmaceuticals


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Safety of Transdermal Selegiline provide antidepressant efficacy without the need for dietary modification?

  • 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 l.jpg
10 mg Oral and 20 mg Transdermal Selegiline provide antidepressant efficacy without the need for dietary modification?

  • 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 l.jpg
Safety of Oral Selegiline (Eldepryl) provide antidepressant efficacy without the need for dietary modification?

  • 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 l.jpg
AERS & IMS Health Records for Oral Selegiline provide antidepressant efficacy without the need for dietary modification?

  • Pharmacovigilance data (1997-2005)

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

    Eldepryl Parnate

    1.56 43.36


Aers 4 reports of hypertensive crisis l.jpg
AERS: 4 Reports of Hypertensive Crisis provide antidepressant efficacy without the need for dietary modification?

  • 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


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DATATOP: Controlled Safety Data provide antidepressant efficacy without the need for dietary modification?

  • 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 l.jpg
DATATOP: provide antidepressant efficacy without the need for dietary modification?Cardiovascular/Cerebrovascular Events


Safety of transdermal selegiline27 l.jpg
Safety of Transdermal Selegiline provide antidepressant efficacy without the need for dietary modification?

  • 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


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Tyramine Challenge Studies provide antidepressant efficacy without the need for dietary modification?

  • 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)


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Tyramine Pressor Test Model provide antidepressant efficacy without the need for dietary modification?

  • Baselinetyraminechallenge

  • Active drugtreatment

  • On-drugtyramine challenge

Endpoint: 30 mmHg SBP


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Model: Minimum Pressor Dose provide antidepressant efficacy without the need for dietary modification?

  • Baselinetyraminechallenge

  • Active drugtreatment

  • On-drugtyramine challenge

  • Example

  • Minimum

  • Pressor

  • dose 200 mg

  • Minimum

  • Pressor

  • dose 400 mg


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Model: Tyramine Sensitivity Factor (TSF) provide antidepressant efficacy without the need for dietary modification?

  • Baselinetyraminechallenge

  • Active drugtreatment

  • On-drugtyramine challenge

  • Example: Drug 1

  • Minimum

  • Pressor

  • dose 200 mg

  • Minimum

  • Pressor

  • dose 400 mg

  • 400/200 = TSF of 2


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Model: Tyramine Sensitivity Factor (TSF) provide antidepressant efficacy without the need for dietary modification?

  • Baselinetyraminechallenge

  • Active drugtreatment

  • On-drugtyramine challenge

  • Example: Drug 2

  • Minimum

  • Pressor

  • dose 10 mg

  • Minimum

  • Pressor

  • dose 400 mg

  • 400/10 = TSF of 40


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Comparator Studies provide antidepressant efficacy without the need for dietary modification?

  • 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)


Tsf transdermal 20 mg vs oral selegiline 10 mg l.jpg

338 provide antidepressant efficacy without the need for dietary modification?± 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)


Tsf of fluoxetine 60 mg l.jpg

338 provide antidepressant efficacy without the need for dietary modification?± 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)


Tsf of tranylcypromine 30 mg parnate l.jpg

10 provide antidepressant efficacy without the need for dietary modification?± 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)


Tsf stability over time 40 mg dose l.jpg

40 mg provide antidepressant efficacy without the need for dietary modification?

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 selegiline38 l.jpg
Safety of Transdermal Selegiline provide antidepressant efficacy without the need for dietary modification?

  • 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


Pharmacodynamic effect of food on pressor dose l.jpg

64 provide antidepressant efficacy without the need for dietary modification?± 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


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Tyramine Content in a High-Tyramine Meal provide antidepressant efficacy without the need for dietary modification?


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Pressor Dose Range at Steady State provide antidepressant efficacy without the need for dietary modification?

Mean Pressor Dose(mg Tyramine)

256

204

10

Tyramine Sensitivity Factor

Transdermal Selegiline 20 mg

21 Days

TransdermalSelegiline 20 mg

30 Days

Tranylcypromine30 mg


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Safety Margin: 20 mg Transdermal, Extremes provide antidepressant efficacy without the need for dietary modification?(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 l.jpg
Tyramine Challenge Program Conclusions provide antidepressant efficacy without the need for dietary modification?

  • 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 selegiline44 l.jpg
Safety of Transdermal Selegiline provide antidepressant efficacy without the need for dietary modification?

  • 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 l.jpg
Phase III Safety provide antidepressant efficacy without the need for dietary modification?

  • 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 l.jpg
Events of Interest Review Process provide antidepressant efficacy without the need for dietary modification?

  • 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


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Analysis of Blood Pressure Increases in provide antidepressant efficacy without the need for dietary modification?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%


Safety conclusions l.jpg
Safety Conclusions provide antidepressant efficacy without the need for dietary modification?

  • 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 l.jpg

Provider / Patient Awareness provide antidepressant efficacy without the need for dietary modification?

Chad VanDenBerg, Pharm.D., BCPP

Director, Clinical Affairs & Product Information

Somerset Pharmaceuticals, Inc.

49


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FDA Question #2 provide antidepressant efficacy without the need for dietary modification?

  • 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 l.jpg
Education Plan provide antidepressant efficacy without the need for dietary modification?

  • 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 l.jpg
Objective and Considerations provide antidepressant efficacy without the need for dietary modification?

  • Primary Objective

    • Dietary modification instructions

  • Implementation Considerations

    • Prevent simultaneous use of multiple patches

    • Appropriate titration instructions


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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 l.jpg
Prescriber Education Dietary Modifications

  • 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


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Pharmacist Education Dietary Modifications

  • Key Elements

    • Educational programs including teleconferences and mailings

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


Patient education l.jpg
Patient Education Dietary Modifications

  • Patient education materials

  • Patient information leaflet

  • Patient starter pack

  • EMSAM website


Slide57 l.jpg

Dietary Modifications Required Dietary Modifications

57


Pharmacovigilance program l.jpg
Pharmacovigilance Program Dietary Modifications

  • Education and outreach program

  • Pharmacovigilance procedures and reporting

  • Targeted follow up on specific adverse events

    • Hypertensive crisis and other CV events


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Provider / Patient Awareness Summary Dietary Modifications

  • Multi-faceted plan

    • Enhanced education program

      • Prescribers

      • Pharmacists

      • Patients

    • Distinctive packaging

    • Enhanced pharmacovigilance


Conclusions l.jpg

Conclusions Dietary Modifications

Melvin Sharoky, MD

CEO and President

Somerset Pharmaceuticals, Inc.

60


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