Informed ConsentInformed ConsentRisk of Cheese ReactionRisk of Cheese Reaction

A possible risk of using selegiline is uncontrolled A possible risk of using selegiline is uncontrolled hypertension (high blood pressure), the so-called hypertension (high blood pressure), the so-called “cheese reaction”, which can occur if you eat foods “cheese reaction”, which can occur if you eat foods containing tyramine, e.g., aged cheese, liquor, dry containing tyramine, e.g., aged cheese, liquor, dry sausage, yogurt, raisins, liver, pickled herring, Fava sausage, yogurt, raisins, liver, pickled herring, Fava beans, sauerkraut, and over-the-counter cough/cold beans, sauerkraut, and over-the-counter cough/cold medications. Therefore, it is important that you tellmedications. Therefore, it is important that you tellyour doctor immediately if you have any of the following your doctor immediately if you have any of the following symptoms: headache, heart palpitations, a sense of symptoms: headache, heart palpitations, a sense of constriction in the throat or chest, sweating, dizziness, constriction in the throat or chest, sweating, dizziness, neck stiffness, nausea, or vomiting.neck stiffness, nausea, or vomiting.

1b - 83

Proposed Label for 30-40 mg Diet (excerpt)Proposed Label for 30-40 mg Diet (excerpt)

ClassClassTyramine FoodsTyramine Foodsto Avoidto Avoid Safe, No or Low TyramineSafe, No or Low Tyramine

Meat, Poultry, FishMeat, Poultry, Fish Aged & SpoiledAged & Spoiled Fresh & Fresh processedFresh & Fresh processed

VegetablesVegetables Fava bean podsFava bean pods All othersAll others

DairyDairy Aged cheesesAged cheeses Processed cheeses, yogurtProcessed cheeses, yogurt

BeveragesBeverages Tap beersTap beersUnpasteurized beersUnpasteurized beers

Alcohol not recommendedAlcohol not recommendedBottled & canned beerBottled & canned beer

MiscellaneousMiscellaneous Marmite, sauerkraut, Marmite, sauerkraut, soy productssoy products

Brewer’s & Baker’s yeastBrewer’s & Baker’s yeastCommercial chain Commercial chain restaurant pizzarestaurant pizza

4a - 8

Patient Information on Dietary ModificationsPatient Information on Dietary Modifications A modified diet is not necessary when taking EMSAM A modified diet is not necessary when taking EMSAM

6mg/24 hours (20mg)6mg/24 hours (20mg)

The consumption of certain foods and beverages during The consumption of certain foods and beverages during treatment with EMSAM 9mg/24 hours (30mg) or treatment with EMSAM 9mg/24 hours (30mg) or 12mg/24 hours (40mg) dose may lead to a sudden, large 12mg/24 hours (40mg) dose may lead to a sudden, large increase in blood pressure, called a ‘‘hypertensive crisis’’ increase in blood pressure, called a ‘‘hypertensive crisis’’ (a potentially life-threatening situation). (See What are the (a potentially life-threatening situation). (See What are the possible side effects of EMSAM?)possible side effects of EMSAM?)

Dietary Modifications:Dietary Modifications:

To prevent a hypertensive crisis, the following foods and To prevent a hypertensive crisis, the following foods and beverages should be avoided beginning on the first day beverages should be avoided beginning on the first day of EMSAM 9mg/24 hours (30mg) or 12mg/24 hours (40mg) of EMSAM 9mg/24 hours (30mg) or 12mg/24 hours (40mg) treatment and continue until 2 weeks after a dose treatment and continue until 2 weeks after a dose reduction to EMSAM 6mg/24 hours (20mg) or stopping reduction to EMSAM 6mg/24 hours (20mg) or stopping EMSAM 9mg/24 hours (30mg) or 12mg/24 hours (40mg):EMSAM 9mg/24 hours (30mg) or 12mg/24 hours (40mg):

4b - 8

Patient Information on Dietary Modifications Patient Information on Dietary Modifications (Continued)(Continued)

Dietary Modifications:Dietary Modifications:

12mg/24 hours (40mg):12mg/24 hours (40mg):

– Air dried, aged and fermented meats, sausages and salamis Air dried, aged and fermented meats, sausages and salamis (including cacciatore, hard salami and mortadella); pickled (including cacciatore, hard salami and mortadella); pickled herring; and any spoiled or improperly stored meat, poultry herring; and any spoiled or improperly stored meat, poultry and fish (e.g., foods that have undergone changes in and fish (e.g., foods that have undergone changes in coloration, odor, or become moldy)coloration, odor, or become moldy)

– Broad bean pods (fava bean pods)Broad bean pods (fava bean pods)

– Aged cheesesAged cheeses

– All varieties of tap beer, and beers that have not been All varieties of tap beer, and beers that have not been pasteurized so as to allow for ongoing fermentation should pasteurized so as to allow for ongoing fermentation should be avoided during EMSAM treatmentbe avoided during EMSAM treatment

– Concentrated yeast extract (e.g., Marmite), sauerkraut, all Concentrated yeast extract (e.g., Marmite), sauerkraut, all soybean products (including soy sauce and tofu)soybean products (including soy sauce and tofu)

All foods must be fresh or properly frozenAll foods must be fresh or properly frozen

Avoid foods when you are unaware of storage conditionsAvoid foods when you are unaware of storage conditions4b - 9

Informed ConsentInformed ConsentDescription of Symptoms of Hypertensive CrisisDescription of Symptoms of Hypertensive Crisis

Severe headache, flushing, sudden elevation of Severe headache, flushing, sudden elevation of blood pressure, awareness of rapid or blood pressure, awareness of rapid or pounding heart, nausea, vomitting, sweating, pounding heart, nausea, vomitting, sweating, fever, and chest pain. Although rare, fever, and chest pain. Although rare, hypertensive crisis may be a life-threatening hypertensive crisis may be a life-threatening reaction that requires immediate medical reaction that requires immediate medical attention.attention.

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Transdermal SelegilineTransdermal SelegilinePivotal Trial II: P0052 Acute MDDPivotal Trial II: P0052 Acute MDD

0%

20%

40%

60%

80%

100%

BLEMSAM

BL Pbo wk5EMSAM

wk5 Pbo wk8EMSAM

wk8 Pbo

40mg

30mg

20mg

HAMD-28: p < 0.03 p <0.04

Dosage

2 - 19

Transdermal SelegilineTransdermal SelegilinePivotal Trial II: P0052 Acute MDDPivotal Trial II: P0052 Acute MDD

0

5

10

15

20

25

30

Baseline wk5 wk8

STS

Pbo

0%

20%

40%

60%

80%

100%

BLEMSAM

BL Pbo wk5EMSAM

wk5 Pbo wk8EMSAM

wk8 Pbo

40 cm2

30 cm2

20 cm2

HAMD-28

p < 0.03 p <0.04

Dosage

2 - 18

Responder Rates* for MDD Patients inResponder Rates* for MDD Patients inPlacebo-Controlled StudiesPlacebo-Controlled Studies

StudyStudy EMSAMEMSAM PlaceboPlacebo

E-106E-106 4242 2727

P0052P0052 4646 3535

P9804P9804 4242 3030

* Defined as CGI-I score of 1 or 2* Defined as CGI-I score of 1 or 2

% Improved% Improved

2 - 11

Tyramine Pressor Dose and TSF Values for Individual Tyramine Pressor Dose and TSF Values for Individual Subjects Challenged in the Fasted and Fed StatesSubjects Challenged in the Fasted and Fed States

Tyramine Pressor Dose (mg)Tyramine Pressor Dose (mg)

SubjectSubject Fasted*Fasted* FedFed Fed/FastedFed/Fasted

11 37.537.5 100100 2.72.7

22 37.537.5 100100 2.72.7

33 5050 200200 4.04.0

44 7575 300300 4.04.0

55 2525 7575 3.03.0

66 2525 100100 4.04.0

77 7575 200200 2.72.7

88 7575 300300 4.04.0

*Fasted - lowest value obtained during 30-90 days of EMSAM 40 mg treatment*Fasted - lowest value obtained during 30-90 days of EMSAM 40 mg treatment 3a - 20