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TYRAMINE SAFETY WITH EMSAM

Gregory M. Dubitsky, MDFDA Division of Psychiatry ProductsOctober 26, 2005

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EMSAM

Transdermal delivery system for selegiline.

Selegiline:

-irreversible inhibitor of monoamine oxidase.

-shows relatively selective inhibition of MAO-B at low clinical doses but selectivity is lost with increasing dose.

-oral formulation (Eldepryl) approved & marketed for Parkinson’s disease for several years.

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PROPOSED INDICATION:

Major depression

Presumed Mechanism: Inhibition of MAO-A + MAO-B in the brain.

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EMSAM Patch Strengths(approx. amount of selegiline

delivered over 24 hours)

20mg/20cm2 (6mg)

30mg/30cm2 (9mg)

40mg/40cm2 (12mg)

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Selegiline Pharmacokinetics(20mg patch vs. 10mg oral)

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KEY ISSUE:

Can low dose transdermal selegiline be safely used without

tyramine restrictions?

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FIRST:

A Short Review of Tyramine

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Sources of Tyramine

Tyramine is formed by the degradation of protein in foods:

Protein → Tyrosine → Tyramine

Thus, it is found in relatively large amounts in many foods that have undergone aging, such as many cheeses.

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Tyramine Pharmacology

Structurally similar to epinephrine & norepinephrine but weaker action.

Once systemically absorbed, it is taken up by adrenergic neurons and displaces NE from synaptic vesicles.

Large amounts of NE are released.

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“Cheese Reaction”

• huge systolic blood pressure increase (mean increase of 55 mmHg) (SBP>DBP)

• increase in pulse, palpitations

• headache

• nausea or vomiting

• diaphoresis

• photophobia

• rare intracerebral bleed, cardiac failure, or death

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Natural Protective MechanismAgainst Excessive Tyramine

Tyramine is metabolized by monoamine oxidase-type A (MAO-A)

Pre-systemic (major role)

• intestinal wall

• liver (first-pass effect)

Systemic (minor role: normally <1%)

• peripheral adrenergic neurons

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Traditional Antidepressant MAOI’s (e.g., tranylcypromine)

Inhibit MAO-A at clinical doses and allow large amounts of tyramine to enter systemic circulation → cheese reaction.

Thus, foods and beverages with high tyramine content are prohibited.

Also, inhibition is irreversible: enzyme “killers.” After TX, MAO-A must be regenerated (2 wks).

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Tyramine-Rich Foods

• aged cheeses• air dried, aged, and fermented meats,

sausages, and salami (e.g., hard salami)• soybean products• tap beer• broad bean pods• sauerkraut• pickled herring

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Effect of Oral Selegiline on MAO-A

Irreversibly inhibits MAO-A in a dose-dependent manner:

• 10mg – minimal inhibition.• 20mg – appreciable inhibition.• 60mg – inhibition approaches tranylcypromine.

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Rationale for Transdermal Delivery of Selegiline

In Theory: Transdermal delivery of selegiline produces only minimal MAO-A inhibition in intestine and liver and, thus, eliminates the need for a tyramine restricted diet.

Does theory translate into safe clinical use?

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Tyramine Challenge Studies

Objective Provide a clinically relevant measure of the

degree of MAO-A inhibition as reflected by the estimated minimum dose of tyramine that produces a clinically significant rise in blood pressure.

Lower minimum tyramine dose = greater inhibition.

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Challenge Study Characteristics

• small N (10-20 subjects).

• young to middle-age healthy volunteers.

• usually under fasted conditions.

• tyramine administered in capsules.

• few included a comparator group.

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Tyramine Dosing Algorithm

Each challenge consisted of a series of successive approximations on 3 consecutive days:

50mg

25mg 100mg

12.5mg 37.5mg 75mg 200mg

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Overall Study Design

Baseline tyramine challenge 1

↓

Baseline tyramine challenge 2

↓

Study drug treatment

↓

On-drug tyramine challenge

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Blood Pressure Assessment

BP assessments

-baseline = mean of 3 consecutive readings.

-after tyramine, BP measured q5 min for 2 hours then q15 min for 4 hours.

BP endpoint

-after tyramine, increase in SBP of 30 mmHg or more compared to pre-tyramine SBP for 3 consecutive readings.

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Outcome Variables of Interest

Pressor Dose or TYR30 = estimated minimum tyramine dose required to produce the BP endpoint at each challenge.

Baseline Pressor Dose = mean of the pressor doses for 2 baseline challenges.

Tyramine Sensitivity Factor (TSF) = ratio of the baseline to the endpoint pressor dose.

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Outcome Interpretation

A lower tyramine pressor dose or a higher TSF implies a greater degree of MAO-A inhibition.

Based on previous studies, tyramine-rich meals are thought to contain no more than approximately 40mg tyramine. Thus, pressor doses of about 40mg or below indicate a risk of a cheese reaction.

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TYRAMINE:

Safety with EMSAM

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Tyramine Challenge Studies (fasting conditions)

Drug (N) Dose/

Duration

Baseline TYR30 (mg)

On-Drug TYR30(mg)

TSF

EMSAM(47)

(3 study pool)

20mg/9-10d 507 298 1.8

EMSAM(12) 20mg/30d 483 204 2.9

EMSAM(10) 30mg/10d 470 210 2.4

EMSAM(12) 40mg/10d 588 198 3.5

EMSAM(18) 40mg/30d 575 84 11.5

Oral Selegiline (21) 5mg bid/9d 529 357 1.7

Tranylcypromine (9) 30mg/8d 400 10 40

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At this point –

FDA and Somerset agree that tyramine restrictions will be recommended with

the 30mg and 40mg patches, based on current data.

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EMSAM 30mg Tyramine Data

Study P0048: EMSAM 30mg for 10 days in 10 healthy subjects (fasted).

• mean pressor doses 470mg (baseline) and 210 (on-EMSAM).

• mean TSF = 2.4.

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Tyramine Pressor Doses after EMSAM 30mg for 10 days (N=10)

0

1

2

3

4

5

6

100mg 200 300 400

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EMSAM 40mg Tyramine Data

Study P0201: EMSAM 40mg for up to 90 days in healthy males.

Data after 40mg × 30 days (fasted):

• mean pressor doses 575mg (baseline) and 84mg (on-EMSAM).

• mean TSF = 11.5.

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Tyramine Pressor Doses after EMSAM 40mg for 30 days (N=18)

0

1

2

3

4

5

6

7

25mg 37.5 50 75 150 200

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Also: Less Clinical Trial Experience with the 30mg & 40mg Patches

Only about one-third of patients in the EMSAM depression program used the 30mg or 40mg patches.

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Outstanding Question –

Should tyramine restrictions will be recommended with the 20mg patch?

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TSF Findings from Tyramine Challenge Studies

• dose-response over the range 20-40mg.

• time-dependency over first 30 days.

• food-effect: food reduces tyramine sensitivity approximately 2-fold.

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Dose-response for TSF

0

2

4

6

8

10

12

9-10days

30 days

20 mg

30 mg

40 mg

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Time-dependency for TSF

0

2

4

6

8

10

12

20mg 40mg

9-10 days

30 days

60 days

90 days

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Food Effect on TSF

0

2

4

6

8

10

12

40mg

Fasting

Fed

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Five Arguments Supporting No Tyramine Restrictions at

the 20mg Dose(and some caveats)

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Argument #1 Mean Pressor Doses with the 20mg Patch

• in the fasted state, mean pressor doses were 200 mg or more.

• in fed state, pressor doses increase approx. 2-fold.

• tyramine-rich meal is expected to contain not more than 40mg of tyramine.

Thus, there appears to be a 10-fold safety margin under fed conditions (400mg/40mg).

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Caveat

Mean pressor doses have limited usefulness in assessing absolute safety.

More Relevant Question:

What is the lower end of the pressor dose range - do any subjects have a pressor dose of about 40mg or below?

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Example: Study P0045

Mean pressor dose (fasted) after EMSAM 20mg for 30 days was 204 mg (N=12).

But, the distribution of pressor doses was:400mg N=1

300mg N=1 200mg N=8 100mg N=1 50mg N=1 (required labetolol rescue)

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Argument #2 Study 9802

Methods

• 12 subjects ingested tyramine-rich meals before & after EMSAM 20mg × 13 days.

• mean estimated tyramine content 323mg (range 244-378mg).

• BP assessments q10 min × 5 hours post-meal.

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Study 9802 Results

Three subjects had one-time SBP increases after EMSAM TX (34, 37, & 84 mmHg).

No subject reached the pressor endpoint (defined as greater than 30 mmHg increase in SBP based on moving averages of 3 consecutive readings).

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Argument #3 TSF with 20mg patch is similar to Eldepryl

A comparison of EMSAM 20mg with Eldepryl (oral selegiline 5mg bid) for 9-10 days revealed comparable TSF’s.

Oral selegiline (Eldepryl) has been marketed for several years without tyramine precautions.

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TSF for 20mg Patch comparable to Eldepryl (oral selegiline)

0

1

2

3

9-10days

20mg Patch

Oral 5mg bid

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Pressor Doses for EMSAM 20mg vs. Eldepryl 5mg bid (9-10 days TX)

0

2

4

6

8

10

12

14

16

18

20

100mg 200 300 400 500 600 700

EMSAM

Eldepryl

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Caveat:

Rare hypertensive reactions have been reported with recommended doses of oral selegiline after ingesting tyramine-containing foods (Eldepryl labeling).

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Argument #4 TSF is much lower than with tranylcypromine

Tranylcypromine treatment produced a mean TSF much higher than with EMSAM 20mg, 30mg, and 40mg.

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All EMSAM TSF’s much smaller than for tranylcypromine

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5

10

15

20

25

30

35

40

8-10days

STS 20mg

STS 30mg

STS 40mg

Tranylcyp.

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Pressor Doses: EMSAM 20mg vs. Tranylcypromine 30mg (8-10 days TX)

(Study P9941)

0

1

2

3

4

5

6

7

8

9

10mg 200 300 400

EMSAM

Tranyl.

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Argument #5 Clinical Trial Safety Data

Over 2,500 patients with depression were treated with EMSAM (20-40mg) without dietary restrictions (820 patient-years of exposure).

No known hypertensive reactions to date.

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Caveat

Blood pressure was not frequently monitored – hypertensive reactions may have been missed.

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Concerns about Approving the 20mg Dose with No Tyramine Restrictions

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Concern #1Pressor Dose Safety Margin

No large difference in the minimum fasted tyramine pressor doses between the lowest and highest patch strengths:

20mg patch - 50mg

40mg patch - 25mg.

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Concern #2 Variability in Tyramine

Sensitivity

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Between-subject Variability

Wide range of pressor doses (Study P0045):

50 to 400 mg.

Individuals at the lower end of the range may be at risk for a hypertensive reaction.

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Within-subject Variability

Differences in pressor doses between 2 baseline tyramine challenges, about 1 week apart (Study P0045):

• 3/12 had a difference of 200 mg.

• 2/12 had a difference of 300 mg.

Thus, risk may vary over time.

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High degree of variability in tyramine sensitivity:

1) requires large safety margin (i.e., pressor doses well above 40mg).

2) makes it unlikely that the tyramine safety profile of the 20mg patch is distinctly different from the 30mg & 40mg patches – a large degree of overlap seems probable.

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Concern #3 Potential for Misuse and

Confusion in the Marketplace

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Approval of the 20mg patch without dietary precautions may lead to:

• non-compliance with dietary measures at higher doses - “If it’s OK at 20mg, it’s probably OK at higher doses.”

• confusion about which doses require dietary precautions – “Is it 20mg or 20 and 30mg that don’t require precautions?”

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Conclusions

On average, EMSAM 20mg patches appear to provide a reasonable safety margin for use without tyramine restrictions.

However, it seems likely that a small proportion of patients at all doses will experience increased tyramine sensitivity to a potentially hazardous degree.

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Recommendation

Tyramine precautions for all doses.