1 tyramine safety with emsam gregory m. dubitsky, md fda division of psychiatry products october 26,...
TRANSCRIPT
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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
0
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.