# Presentation: 493766

## Selegiline Transdermal System (STS)

**Selegiline Transdermal System **(STS)

- FDA Psychopharmacologic Drugs Advisory Committee

- October 26, 2005

## Introduction

**Melissa Goodhead, BSc, RAC**
**Group Director, Regulatory Affairs / Quality Assurance****Somerset Pharmaceuticals**

## 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.**

## 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**

## Overview

**Sheldon Preskorn, MD**
**Chairman, Department of Psychiatry****University of Kansas, Wichita**

## 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 versus Transdermal Delivery**

**20 mg ****patch**

**skin**

**Oral MAOI**

**Transdermal Selegiline**

## Inhibition of MAO by Selegiline in Guinea Pigs 

**Inhibition of MAO by Selegiline in Guinea Pigs **

**Oral Selegiline**

**Transdermal Selegiline**

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

## Positive Placebo-controlled Efficacy Trialswith Transdermal Selegiline

|  | 
E106 | P0052 | P9806 |
| --- | --- | --- | --- |
| Duration | 6 weeks | 8 weeks | 52 weeks |
| N | 176 | 265 | 322 |
| EMSAM Dose |  20 mg |  20, 30, or 40 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

## Safety – Tyramine

**Lawrence Blob, MD**
**Medical Director, ****Somerset Pharmaceuticals**

## Safety of Transdermal Selegiline 

**Oral selegiline: 16 years of safe use with****normal 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**
**	****	****Eldepryl****	****Parnate**
**	****	****1.56****	****43.36**

## 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

| Incidence per
1000 patient-years | Oral Selegiline | Placebo |
| --- | --- | --- |
| MI | 6.4 | 8.1 |
| CVA / TIA | 6.7 | 13.0 |

## Safety of Transdermal Selegiline 

**Oral selegiline: 16 years of safe use with****normal 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**

## 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

**Endpoint:     30 mmHg SBP**

**Baseline****tyramine****challenge**

**Active ****drug****treatment**

**On-drug****tyramine challenge**

## Model:  Minimum Pressor Dose

**Example**

**Minimum**
**Pressor**
**dose 200 mg**

**Minimum**
**Pressor**
**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**

## Model:  Tyramine Sensitivity Factor (TSF)

**Example: Drug 1**

**400/200 = TSF of 2**

**Minimum**
**Pressor**
**dose 200 mg**

**Minimum**
**Pressor**
**dose 400 mg**

**Baseline****tyramine****challenge**

**Active ****drug****treatment**

**On-drug****tyramine challenge**

## Model:  Tyramine Sensitivity Factor (TSF)

**Example: Drug 2**

**Minimum**
**Pressor**
**dose 10 mg**

**Minimum**
**Pressor**
**dose 400 mg**

**400/10 = TSF of 40**

**Baseline****tyramine****challenge**

**Active ****drug****treatment**

**On-drug****tyramine challenge**

## 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)**

## TSF: Transdermal 20 mg vs. Oral Selegiline 10 mg

**Mean Pressor Dose****(mg Tyramine)**

**338**

**385**

**1.75 ****± 0.54**

**1.67 ****± 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**

## TSF of Fluoxetine 60 mg

**Tyramine Sensitivity Factor**

**338**

**385**

**Fluoxetine**
**60 mg**

**408**

**1.43 ****± 0.56**

**1.75 ****± 0.54**

**1.67 ****± 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)**

## TSF of Tranylcypromine 30 mg (Parnate)

**270**

**10**

**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**

## TSF Stability Over Time (40 mg dose)

**Tyramine Sensitivity Factor**

**84**

**66**

**88**

**10**

**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**

**Mean Pressor Dose****(mg Tyramine)**

## Safety of Transdermal Selegiline 

**Oral selegiline: 16 years of safe use with****normal 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 

**(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**

**Transdermal Selegiline****40 mg**
**Fed**

**64**

**172**

**Mean Pressor Dose**

***p***** = 0.0023**

## 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
    Danish blue
Pinot Noir | 700
454
454
250
454
150

30
30
700 | 1.0
16.7
1.9
1.8
3.2
3.0

1.4
8.8
2.0 |
| Total tyramine in meal |  | 39.8 |

## Pressor Dose Range at Steady State 

**Transdermal Selegiline**** 20 mg**
**21 Days**

**Tranylcypromine****30 mg**

**10**

**Tyramine Sensitivity Factor**

**Mean Pressor Dose****(mg Tyramine) **

**Transdermal****Selegiline**** 20 mg**
**30 Days**

**204**

**256**

**Pressor Dose Range at Steady State **

## 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**

## 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 with****normal 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 Selegiline**__**	**__**	**__**Placebo**_
**	****	****	****1.4% ****	****	****	****	****   1.9%**
**Incidence of AE Hypertension**
**     **_**Transdermal Selegiline**__**	**__**	**__**Placebo**_
**	****	****	****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.**

## 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 dietary****modifications 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 modifications***** *****required***** 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

**Dietary Modifications Required**

## 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.**