1 / 60

TYRAMINE SAFETY WITH EMSAM

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.

kana
Download Presentation

TYRAMINE SAFETY WITH EMSAM

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. TYRAMINE SAFETY WITH EMSAM Gregory M. Dubitsky, MD FDA Division of Psychiatry Products October 26, 2005

  2. 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.

  3. PROPOSED INDICATION:Major depressionPresumed Mechanism: Inhibition of MAO-A + MAO-B in the brain.

  4. EMSAM Patch Strengths(approx. amount of selegiline delivered over 24 hours) 20mg/20cm2 (6mg) 30mg/30cm2 (9mg) 40mg/40cm2 (12mg)

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

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

  7. FIRST:A Short Review of Tyramine

  8. 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.

  9. 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.

  10. “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

  11. 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

  12. 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).

  13. 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

  14. 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.

  15. 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?

  16. 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.

  17. 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.

  18. Tyramine Dosing AlgorithmEach challenge consisted of a series of successive approximations on 3 consecutive days:

  19. Overall Study Design Baseline tyramine challenge 1 ↓ Baseline tyramine challenge 2 ↓ Study drug treatment ↓ On-drug tyramine challenge

  20. 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.

  21. 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.

  22. 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.

  23. TYRAMINE: Safety with EMSAM

  24. Tyramine Challenge Studies (fasting conditions)

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

  26. 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.

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

  28. 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.

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

  30. 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.

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

  32. 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.

  33. Dose-response for TSF

  34. Time-dependency for TSF

  35. Food Effect on TSF

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

  37. 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).

  38. 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?

  39. 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)

  40. 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.

  41. 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).

  42. 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.

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

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

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

  46. Argument #4 TSF is much lower than with tranylcypromine Tranylcypromine treatment produced a mean TSF much higher than with EMSAM 20mg, 30mg, and 40mg.

  47. All EMSAM TSF’s much smaller than for tranylcypromine

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

  49. 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.

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

More Related