# Presentation: 089098

## TYRAMINE SAFETY WITH EMSAM

- Gregory M. Dubitsky, MD
- FDA Division of Psychiatry Products
- October 26, 2005

## 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.

## PROPOSED INDICATION:Major depressionPresumed Mechanism:  Inhibition of MAO-A + MAO-B in the brain.

## EMSAM Patch Strengths(approx. amount of selegiline delivered over 24 hours)

- 20mg/20cm2	(6mg)
- 30mg/30cm2  (9mg)
- 40mg/40cm2	(12mg)

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

## KEY ISSUE:Can low dose transdermal selegiline be safely used without tyramine restrictions?

## FIRST:A Short Review of Tyramine

## 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.

## 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.

## “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

## Natural Protective MechanismAgainst 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

## 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).

## 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

## 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.

## 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?**

## 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.

## 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.

## Tyramine Dosing AlgorithmEach challenge consisted of a series of successive approximations on 3 consecutive days:

## Overall Study Design

**Baseline tyramine challenge 1**
- ↓
**Baseline tyramine challenge 2**
- ↓
**Study drug treatment**
- ↓
**On-drug tyramine challenge**

## 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.

## 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.

## 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.

## TYRAMINE: Safety with EMSAM

## 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 |

## At this point –FDA and Somerset agree that tyramine restrictions will be recommended with the 30mg and 40mg patches, based on current data.

## 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.

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

## 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.

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

## 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.

## Outstanding Question –Should tyramine restrictions will be recommended with the 20mg patch?

## 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.

## Dose-response for TSF 

## Time-dependency for TSF

## Food Effect on TSF 

## Five Arguments Supporting No Tyramine Restrictions at the 20mg Dose(and some caveats) 

## 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).

## 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?

## 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)

## 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.

## 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).

## 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.

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

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

## Caveat:

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

## Argument #4 TSF is much lower than with tranylcypromine

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

## All EMSAM TSF’s much smaller than for tranylcypromine

## Pressor Doses:  EMSAM 20mg vs. Tranylcypromine 30mg (8-10 days TX)(Study P9941)

## 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.

## Caveat

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

## Concerns about Approving the 20mg Dose with No Tyramine Restrictions

## Concern #1Pressor 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.

## Concern #2 Variability in Tyramine Sensitivity

## 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.

## 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.

## 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.

## Concern #3 Potential for Misuse and Confusion in the Marketplace

## 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?”

## 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.

## Recommendation

**Tyramine precautions for all doses.**