Selegiline Patch (Emsam)
9 & 12 mg/24h: Tyramine diet required
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major Depressive Disorder (MDD) | Adults | Monotherapy | FDA Approved |
The selegiline transdermal system (Emsam) is the first and only transdermal MAOI approved for the treatment of MDD, receiving FDA approval in 2006. Unlike oral MAOIs (phenelzine, tranylcypromine), it is indicated as a potential first-line option — the PI does not restrict it to treatment-resistant patients. Its unique pharmacokinetic profile allows the 6 mg/24h dose to be used without any dietary tyramine restrictions, a breakthrough that addresses the primary barrier to MAOI prescribing. At the lowest effective dose, transdermal delivery bypasses the gastrointestinal tract, preserving intestinal MAO-A activity and allowing dietary tyramine to be metabolised before reaching the systemic circulation. At higher doses (9 and 12 mg/24h), systemic selegiline levels are sufficient to partially inhibit intestinal MAO-A, necessitating tyramine dietary restrictions.
Treatment-resistant depression — Used when oral antidepressants have failed; the transdermal route offers an alternative to oral MAOIs with a more favourable safety profile at 6 mg. (Evidence quality: Moderate)
Atypical depression — MAOIs remain highly effective for this subtype; the transdermal route may improve adherence. (Evidence quality: Low – extrapolated from oral MAOI data)
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MDD — initial treatment | 6 mg/24h patch | 6 mg/24h | 12 mg/24h | 6 mg/24h is the starting AND target dose; no dietary restrictions at this dose Increase by 3 mg/24h every ≥2 weeks if needed; full effect may be delayed |
| MDD — inadequate response at 6 mg | 9 mg/24h patch | 9–12 mg/24h | 12 mg/24h | Tyramine dietary restrictions begin on first day of 9 mg or 12 mg dosing Restrictions continue for 2 weeks after dose reduction to 6 mg or discontinuation |
Application Instructions
| Parameter | Instruction |
|---|---|
| Application site | Dry, intact skin on upper torso (below neck, above waist), upper thigh, or outer surface of upper arm |
| Frequency | Apply one patch every 24 hours; replace at approximately the same time each day |
| Site rotation | Do not apply to the same site on consecutive days |
| Patch handling | Do not cut the patch; do not wear more than one patch at a time; avoid touching the adhesive side |
| Heat avoidance | Do not expose the application site to heating pads, electric blankets, saunas, hot tubs, or prolonged direct sunlight (may increase drug absorption) |
Special Population Adjustments
| Population | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Elderly (≥65 years) | 6 mg/24h | 6 mg/24h (recommended) | Per clinical judgement | Recommended dose is 6 mg/24h daily (PI Section 8.5) Age effect on PK not systematically evaluated |
| Renal impairment | No adjustment needed (mild/moderate/severe) | PK unaffected by renal impairment; not studied in ESRD (PI Section 8.8) | ||
| Hepatic impairment | No adjustment for mild/moderate | No PK differences observed; not studied in severe hepatic impairment (PI Section 8.7) | ||
| Paediatric (<12 years) | Contraindicated | Increased risk of hypertensive crisis; children may have higher selegiline exposure (PI Section 8.4) | ||
| Adolescents (12–17 years) | Not recommended | Efficacy not demonstrated in paediatric MDD trial (PI Section 8.4) | ||
The transdermal route delivers selegiline directly into the systemic circulation, bypassing first-pass metabolism in the GI tract and liver. Since intestinal MAO is predominantly type A, and MAO-A is the enzyme responsible for metabolising dietary tyramine in the gut wall, the transdermal route preserves this intestinal “tyramine firewall” at lower doses. At 6 mg/24h, systemic selegiline concentrations are sufficient to inhibit both MAO-A and MAO-B in the brain (producing antidepressant effects) but not high enough to significantly inhibit intestinal MAO-A. At higher doses (9 and 12 mg/24h), systemic levels rise sufficiently to partially inhibit intestinal MAO-A, restoring the tyramine risk and necessitating dietary restrictions.
Selegiline Patch Pharmacology
Mechanism of Action
Selegiline is an irreversible inhibitor of monoamine oxidase with preferential affinity for MAO-B at low concentrations. However, at the doses used for depression (6–12 mg/24h transdermally), selegiline inhibits both MAO-A and MAO-B in the brain. Antidepressant activity in animal models (Forced Swim Test) was observed only at doses that inhibited both isoenzymes. By preventing the catabolism of serotonin, norepinephrine, dopamine, and phenylethylamine in the CNS, selegiline increases monoamine neurotransmitter availability. In vitro receptor binding studies also demonstrate selegiline affinity for the human α2B adrenergic receptor (Ki = 0.3 μM), suggesting an additional pharmacological mechanism. Importantly, the transdermal route delivers significantly higher selegiline exposure with significantly lower exposure to metabolites (including methamphetamine and amphetamine, which are produced by oral selegiline but minimised with transdermal delivery).
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Transdermal; 25–30% of patch content delivered systemically over 24 h (range ~10–40%); bypasses GI and hepatic first-pass metabolism | GI MAO-A preserved at 6 mg/24h, enabling tyramine-free dining; interindividual variability in absorption (10–40%); avoid heat exposure at application site |
| Distribution | Not formally characterised for transdermal route; oral selegiline protein binding ~90% | Selegiline is highly lipophilic, facilitating CNS penetration and transdermal absorption |
| Metabolism | Transdermal route produces significantly lower metabolite levels vs oral; oral selegiline metabolised to desmethylselegiline, methamphetamine, and amphetamine via CYP2B6 and CYP3A4 | Reduced exposure to amphetamine/methamphetamine metabolites is a key advantage of the patch; carbamazepine increases selegiline levels ~2-fold (contraindicated) |
| Elimination | Primarily renal (as metabolites); renal impairment does not affect PK; no clinically relevant CYP interactions at standard doses | No dose adjustment needed for renal impairment (mild/moderate/severe); ketoconazole, alprazolam, ibuprofen, olanzapine, and warfarin do not require dose adjustments when co-administered |
Side Effects
Adverse reaction data are from the pooled short-term, placebo-controlled EMSAM clinical trials (PI Section 6.1; N=2,036 selegiline exposures). The side-effect profile is considerably more favourable than oral MAOIs, with application site reactions being the most distinctive adverse event.
| Adverse Effect | Incidence (EMSAM vs Placebo) | Clinical Note |
|---|---|---|
| Application site reaction | 24% vs 12% | Itching, redness, swelling at patch site; usually mild-to-moderate and resolves within hours of patch removal; rotate application sites daily (PI Section 6.1) |
| Headache | 18% vs 17% | Rate similar to placebo; distinguish from hypertensive crisis headache (occipital, sudden onset) (PI Sections 5.3, 6.1) |
| Insomnia | 12% vs 7% | Consider applying patch earlier in the day if sleep is affected (PI Section 6.1) |
| Adverse Effect | Incidence (EMSAM vs Placebo) | Clinical Note |
|---|---|---|
| Diarrhea | 9% vs 7% | Usually self-limiting (PI Section 6.1) |
| Dry mouth | 8% vs 6% | Less prominent than with oral MAOIs (PI Section 6.1) |
| Dyspepsia | 4% vs 3% | GI effects milder than oral route (PI Section 6.1) |
| Rash | 4% vs 2% | Distinct from application site reaction; assess for hypersensitivity (PI Section 6.1) |
| Pharyngitis | 3% vs 2% | Upper respiratory symptoms (PI Section 6.1) |
| Sinusitis | 3% vs 1% | (PI Section 6.1) |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hypertensive crisis (at 9 & 12 mg/24h with tyramine) | Rare (with dietary compliance) | Minutes to hours after tyramine ingestion | Discontinue patch; treat hypertensive emergency; ED admission (PI Section 5.3) |
| Serotonin syndrome | Rare (with contraindicated drug) | Hours after exposure to serotonergic agent | Discontinue all serotonergic agents; supportive care (PI Section 5.2) |
| Suicidal ideation / behaviour | Uncommon (age-dependent) | First weeks to months | Close monitoring; consider stopping if emergent suicidality (PI Section 5.1) |
| Mania / hypomania | 0.4% (8/2,036 in Phase III) | First weeks | Discontinue; screen for bipolar disorder (PI Section 5.4) |
Compared with oral MAOIs (phenelzine, tranylcypromine), the selegiline patch has a notably milder side-effect profile. Orthostatic hypotension, weight gain, and sexual dysfunction — the major tolerability issues with oral MAOIs — were not significantly more common than placebo in EMSAM trials. The most distinctive adverse event is application site reaction (24%), which is usually mild and transient. This favourable tolerability profile, combined with no dietary restrictions at 6 mg/24h, makes the selegiline patch a significantly more practical MAOI option for many patients.
Drug Interactions
Although the selegiline patch has fewer dietary interactions at the lowest dose, it retains the full range of drug-drug interactions common to all MAOIs. Notably, the contraindicated drug list is specific to EMSAM and does not include ALL tricyclic antidepressants — only clomipramine and imipramine are listed. Carbamazepine raises selegiline levels approximately 2-fold and is contraindicated. Several drugs that do not interact with EMSAM have been specifically studied (alprazolam, ibuprofen, levothyroxine, olanzapine, risperidone, warfarin, ketoconazole) and require no dose adjustment.
Monitoring
- Blood PressureEvery visit; especially at 9 & 12 mg
RoutineMonitor for hypertensive episodes especially if sympathomimetic agents are co-prescribed or if taking 9/12 mg dose. Less orthostatic hypotension risk than oral MAOIs. - Application SiteEach patch change
RoutineAssess for erythema, itching, swelling. Reactions are usually mild and transient (PI Section 6.1). Rotate sites daily. - Mental StateEvery visit for first 3 months
RoutineMonitor for suicidality, mania/hypomania (0.4% in trials), agitation. Screen for bipolar disorder before initiation (PI Sections 5.1, 5.4). - Dietary ComplianceEvery visit if on 9 or 12 mg
Trigger-BasedNot required at 6 mg/24h. At 9 and 12 mg, review tyramine-restricted diet at every visit. Restrictions continue for 2 weeks after stepping down to 6 mg or stopping (PI Section 2.3). - Heat ExposureEach visit
RoutineRemind patients to avoid heating pads, saunas, prolonged sunlight on patch site. Heat may increase drug absorption and elevate selegiline levels (PI Section 5.5).
Contraindications & Cautions
Absolute Contraindications
- Patients <12 years of age — increased risk of hypertensive crisis (higher selegiline exposure) (PI Section 4)
- Pheochromocytoma — MAOIs may precipitate hypertensive crisis (PI Section 4)
- Concurrent or recent use of contraindicated drugs: SSRIs, SNRIs, clomipramine, imipramine, meperidine, tramadol, methadone, pentazocine, propoxyphene, dextromethorphan, carbamazepine (PI Section 4)
- Oral selegiline — patients should not use oral selegiline while on EMSAM (PI Section 17)
Relative Contraindications (Specialist Input Recommended)
- Bipolar disorder (unscreened) — risk of mania/hypomania (0.4% in trials) (PI Section 5.4)
- Adolescents (12–17 years) — not recommended; efficacy not demonstrated (PI Section 8.4)
Use with Caution
- Severe hepatic impairment — not studied (PI Section 8.7)
- ESRD / dialysis — not studied (PI Section 8.8)
- Patients taking sympathomimetic agents or buspirone — BP monitoring required (PI Section 5.3)
- Patients exposed to external heat sources — may increase drug absorption (PI Section 5.5)
Antidepressants increase the risk of suicidal thinking and behaviour in paediatric and young adult patients. In pooled analyses, the risk was 14 additional patients per 1,000 treated (<18 years) and 5 additional per 1,000 (18–24 years). EMSAM is contraindicated in patients less than 12 years of age because of an increased risk of hypertensive crisis.
Patient Counselling
Purpose of Therapy
Emsam is a skin patch that delivers selegiline, a medication that increases mood-regulating brain chemicals by preventing their breakdown. It works differently from most antidepressants and is applied to the skin once daily. At the lowest dose (6 mg/24h), you do not need to follow any special diet. If your doctor increases the dose, certain foods will need to be avoided.
How to Use
Apply one patch daily to dry, clean skin on your upper body, upper thigh, or outer upper arm. Replace the patch at approximately the same time each day. Use a different area of skin each day — do not reuse the same spot on consecutive days. Do not cut the patch. Wash your hands after handling the patch.
Sources
- EMSAM (selegiline transdermal system) — Full Prescribing Information. Revised May 2020. Somerset Pharmaceuticals Inc. DailyMedPrimary source for all dosing, dietary modification rules, adverse reaction incidence (Table 2, N=2,036), contraindications, PK data, and clinical trial results.
- Bodkin JA, Amsterdam JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry. 2002;159(11):1869–1875. DOIPivotal 6-week RCT (Study 1) demonstrating selegiline patch 6 mg/24h superiority over placebo (HAM-D change −9 vs −6.5).
- Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry. 2003;64(2):208–214. DOI8-week RCT (Study 2) showing selegiline patch efficacy at 6–12 mg/24h without dietary restrictions at 6 mg.
- Amsterdam JD, Bodkin JA. Selegiline transdermal system in the prevention of relapse of major depressive disorder: a 52-week, double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2006;26(6):579–586. DOI52-week relapse-prevention study (Study 3). Relapse: 16.8% EMSAM vs 29.4% placebo at week 26 (P=0.005); 17% vs 30.7% at week 52 (P=0.003).
- American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, 3rd ed. Am J Psychiatry. 2010;167(10 Suppl):1–152. DOIAPA guideline referencing MAOIs including transdermal selegiline as treatment options for MDD.
- Azzaro AJ, Ziemniak J, Kemper E, Campbell BJ, VanDenBerg C. Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h): a comparison with oral selegiline capsules. J Clin Pharmacol. 2007;47(10):1256–1267. DOIPK study demonstrating transdermal delivery produces higher selegiline and lower metabolite exposure vs oral, confirming the pharmacological basis for reduced tyramine interaction at 6 mg/24h.
- Azzaro AJ, Ziemniak J, Kemper E, et al. Selegiline transdermal system: an examination of the potential for CYP450-dependent pharmacokinetic interactions with 3 psychotropic medications. J Clin Pharmacol. 2007;47(2):146–158. DOIPK interaction study confirming no clinically relevant interactions between EMSAM and alprazolam, olanzapine, or risperidone.
- Robinson DS, Gilmor ML, Yang Y, Moonsammy G, Azzaro AJ, Oren DA, Campbell BJ. Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials. Psychopharmacology (Berl). 2007;190(3):397–408. DOIMeta-analysis of EMSAM short-term trials confirming efficacy across symptom domains of MDD.
- Lee KC, Chen JJ. Transdermal selegiline for the treatment of major depressive disorder. Neuropsychiatr Dis Treat. 2007;3(5):527–537. PMCComprehensive review of EMSAM efficacy, safety, PK properties, and drug-drug interactions for MDD treatment.
- Patkar AA, Pae CU, Grier DK, Gabbard R, Masand PS. Selegiline transdermal system: a review of its use in major depressive disorder. Drugs Today (Barc). 2007;43(6):361–377. DOIClinical review discussing EMSAM’s pharmacology, tyramine sensitivity data, and practical prescribing considerations.