TYRAMINE SAFETY WITH EMSAM

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TYRAMINE SAFETY WITH EMSAM

• Gregory M. Dubitsky, MD
• FDA Division of Psychiatry Products
• October 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 Parkinsons disease for several years.

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PROPOSED INDICATIONMajor depressionPresumed
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 ISSUECan low dose transdermal selegiline
be safely used without tyramine restrictions?
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FIRSTA 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) (SBPgtDBP)
• 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 lt1)
• peripheral adrenergic neurons

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Traditional Antidepressant MAOIs (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 AlgorithmEach challenge
consisted of a series of successive
approximations on 3 consecutive days
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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 (N10)
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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 (N18)
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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
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Time-dependency for TSF
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Food Effect on TSF
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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 (N12).
• But, the distribution of pressor doses was
• 400mg N1
• 300mg N1
• 200mg N8
• 100mg N1
• 50mg N1 (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 TSFs.
• 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)
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Pressor Doses for EMSAM 20mg vs. Eldepryl 5mg bid
(9-10 days TX)
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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 TSFs much smaller than for
tranylcypromine
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Pressor Doses EMSAM 20mg vs. Tranylcypromine
30mg (8-10 days TX)(Study P9941)
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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 its OK at 20mg, its probably OK at
  higher doses.
• confusion about which doses require dietary
  precautions Is it 20mg or 20 and 30mg that
  dont 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.