Selegiline (Transdermal)

Indications

• FDA-approved for the treatment of major depressive disorder in adults, delivered as a once-daily transdermal system.
• Practical option for patients who need MAO inhibition but cannot reliably follow a tyramine-restricted diet at the 6 mg strength.
• Off-label for treatment-resistant depression, atypical depression, and depression with prominent anergia and hypersomnia.
• Off-label for social anxiety disorder, extrapolating from oral MAO inhibitor evidence rather than transdermal trial data.
• Oral selegiline is approved for Parkinson disease, but the transdermal system is not indicated or dosed for that condition.
• Safety and effectiveness in pediatric patients have not been established, and pediatric trials did not demonstrate efficacy.

Mechanism of action

• Irreversibly inhibits MAO-A and MAO-B in the brain, raising synaptic serotonin, norepinephrine, and dopamine as with oral MAO inhibitors.
• Transdermal delivery bypasses the gastrointestinal tract, so intestinal MAO-A remains largely intact and dietary tyramine is still degraded.
• That preserved gut metabolism is why the 6 mg/24 h patch requires no dietary tyramine restriction in the current US label.
• At 9 and 12 mg/24 h the higher systemic exposure begins to inhibit gut MAO-A, so a tyramine-restricted diet becomes mandatory.
• Selegiline is selective for MAO-B at low oral doses, but the concentrations achieved transdermally inhibit both isoenzymes centrally.

Pharmacokinetics

• About 25 to 30 percent of the patch content is absorbed over 24 hours, giving far higher systemic exposure than an equal oral dose.
• Elimination half-life is roughly 18 to 25 hours, and steady state is reached after approximately 5 days of daily patch changes.
• Metabolized by CYP2B6, CYP2C19, and CYP3A4 to N-desmethylselegiline, l-amphetamine, and l-methamphetamine.
• Those amphetamine metabolites can cause a positive amphetamine result on urine drug immunoassays and require confirmatory testing.
• Heat sources such as heating pads, saunas, and prolonged direct sun over the patch can increase absorption and should be avoided.

Dosing

• Start at 6 mg/24 h applied to dry intact skin on the upper torso, upper thigh, or outer upper arm, and change the patch daily.
• Increase in 3 mg/24 h increments no more often than every 2 weeks, to a maximum of 12 mg/24 h in adults.
• No dietary tyramine restriction is required at 6 mg/24 h; a tyramine-restricted diet is mandatory at 9 and 12 mg/24 h.
• Rotate application sites daily and do not reapply to the same site for several days to limit local skin reactions.
• In older adults or those with hepatic or renal impairment, remain at 6 mg/24 h unless a higher dose is clearly needed.
• Discontinue at least 10 days before elective surgery, and observe a 14-day washout before any serotonergic agent is started.

Adverse effects

• Application site reactions occur in roughly 24 percent of patients versus 12 percent with placebo and are the most common complaint.
• Headache, insomnia, diarrhea, dry mouth, and dyspepsia are the other frequent adverse events reported in registration trials.
• Orthostatic hypotension occurs but is less prominent than with oral phenelzine or tranylcypromine at comparable efficacy.
• Sexual dysfunction and weight gain are notably less frequent than with oral MAO inhibitors or with SSRIs at usual doses.
• Hypertensive crisis can still occur if a contraindicated sympathomimetic or serotonergic agent is added, regardless of patch strength.
• Serotonin syndrome remains a fatal risk with concurrent serotonergic drugs and is not mitigated by transdermal delivery.

Monitoring

• Check blood pressure supine and standing at each visit, particularly during titration above the 6 mg/24 h starting strength.
• Confirm and document dietary counseling whenever the dose is raised to 9 or 12 mg/24 h, since restrictions then apply.
• Inspect application sites and rotate them daily; persistent dermatitis may require topical treatment or discontinuation.
• Review all prescription, over-the-counter, and herbal products at every visit because pharmacodynamic interactions drive serious harm.
• Warn patients and testing programs that urine immunoassays may read positive for amphetamine because of metabolite formation.

Interactions

• Contraindicated with SSRIs, SNRIs, tricyclics, bupropion, mirtazapine, meperidine, tramadol, methadone, and St. John's wort.
• Contraindicated with carbamazepine, oxcarbazepine, cyclobenzaprine, dextromethorphan, linezolid, methylene blue, and buspirone.
• Requires a 14-day washout in both directions with most antidepressants and a 5-week washout after stopping fluoxetine.
• Contraindicated with sympathomimetic amines including pseudoephedrine, phenylephrine, amphetamines, and with pheochromocytoma.
• Avoid tyramine-rich foods entirely at 9 and 12 mg/24 h, and avoid supplements containing tyramine or phenylalanine at any dose.

Special populations

• Human pregnancy data are limited; animal studies show developmental toxicity, so use only if the benefit clearly outweighs the risk.
• Lactation data are essentially absent and the amphetamine metabolites raise theoretical concern, so alternatives are preferred.
• Pediatric trials did not establish efficacy, and adolescents carry the class suicidality warning if the drug is used off-label.
• In adults 65 and older, exposure is higher and the label advises maintaining the 6 mg/24 h dose rather than escalating.
• No specific renal or hepatic dose adjustment is defined, but mild to moderate impairment raises exposure and argues for the lowest strength.

Clinical pearls

• Only the 6 mg/24 h patch is diet-free; 9 and 12 mg/24 h require full tyramine restriction.
• Metabolites can trigger a positive urine amphetamine screen; confirm with mass spectrometry.
• Stop the patch at least 10 days before elective surgery involving general anesthesia.