Selegiline
selegiline hydrochloride — Brand names: Eldepryl, Zelapar, EMSAM
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Parkinson disease — adjunctive therapy (deteriorating response to levodopa/carbidopa) | Adults | Adjunctive to levodopa/carbidopa | FDA Approved |
| Major depressive disorder (EMSAM transdermal only) | Adults | Monotherapy | FDA Approved |
Selegiline occupies a unique clinical niche: at low oral doses it functions as a selective, irreversible MAO-B inhibitor used to extend the wearing-off interval in patients on levodopa, while the transdermal formulation delivers enough drug to inhibit both MAO-A and MAO-B, conferring antidepressant efficacy with a more favorable dietary restriction profile at the lowest patch strength. The oral capsule (Eldepryl) and ODT (Zelapar) are approved exclusively for Parkinson disease, whereas EMSAM is approved only for major depressive disorder.
Early Parkinson disease (monotherapy): Selegiline has been studied as initial monotherapy in early PD to delay the need for levodopa initiation. Several trials, including the DATATOP study, showed modest symptomatic benefit and a delay in requiring levodopa. Evidence quality: Moderate
Attention-deficit hyperactivity disorder (ADHD): Small controlled trials in children have suggested benefit comparable to methylphenidate on attention and hyperactivity measures; however, data remain limited. Evidence quality: Low
Treatment-resistant / atypical depression (oral): Oral selegiline at higher-than-standard doses has been used for atypical depression features, though this use carries the full dietary restriction burden of non-selective MAOIs. Evidence quality: Moderate
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| PD with levodopa wearing-off — oral capsule (Eldepryl) | 5 mg BID | 5 mg BID | 10 mg/day | Give with breakfast and lunch; may allow levodopa dose reduction of 10–30% Higher doses lose MAO-B selectivity |
| PD with levodopa wearing-off — ODT (Zelapar) | 1.25 mg QAM | 1.25–2.5 mg QAM | 2.5 mg/day | Place on tongue before breakfast, no food/liquid 5 min before or after; increase to 2.5 mg after ≥6 weeks if needed Buccal absorption bypasses first-pass metabolism |
| Major depressive disorder — transdermal (EMSAM) | 6 mg/24 h patch | 6–12 mg/24 h patch | 12 mg/24 h | Apply to upper torso, upper thigh, or outer upper arm once daily; increase by 3 mg/24 h q2wk if needed 6 mg/24 h: no dietary tyramine restrictions required |
| MDD — switching from another antidepressant | 6 mg/24 h patch | 6–12 mg/24 h | 12 mg/24 h | Washout 4–5 half-lives of prior drug before starting EMSAM; fluoxetine requires ≥5 weeks washout When stopping EMSAM, wait ≥2 weeks before starting another antidepressant |
Hepatic and Renal Impairment (ODT — Zelapar)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Mild–moderate hepatic impairment (Child-Pugh 5–9) | 1.25 mg QAM | 1.25 mg QAM | 1.25 mg/day | Do not escalate beyond 1.25 mg; avoid in severe hepatic impairment (Child-Pugh >9) |
| Mild–moderate renal impairment (CrCl 30–89) | 1.25 mg QAM | 1.25–2.5 mg QAM | 2.5 mg/day | Standard dose range; not recommended if CrCl <30 mL/min or ESRD |
At the 6 mg/24 h EMSAM dose, intestinal MAO-A remains sufficiently active to metabolize dietary tyramine, so tyramine-rich food restrictions are not required. However, at 9 mg/24 h or 12 mg/24 h, patients must follow a low-tyramine diet throughout treatment and for two weeks after dose reduction to 6 mg/24 h or after discontinuation. For oral selegiline at approved PD doses (≤10 mg/day), MAO-B selectivity is generally preserved and routine tyramine restrictions are not formally required, though rare hypertensive reactions have been reported.
Pharmacology
Mechanism of Action
Selegiline acts as an irreversible, suicide-substrate inhibitor of monoamine oxidase. At low oral doses (5–10 mg/day), it demonstrates high selectivity for MAO-B, the predominant isoform in the basal ganglia and striatum, where it prevents dopamine catabolism and prolongs the duration of levodopa’s therapeutic effect. This selectivity is dose-dependent: at higher doses or with transdermal delivery, selegiline additionally inhibits MAO-A, increasing brain serotonin and norepinephrine levels — the basis for its antidepressant activity. Selegiline also functions as a catecholaminergic activity enhancer, augmenting impulse-evoked release of norepinephrine and dopamine through a mechanism involving trace amine-associated receptor 1 (TAAR1) agonism. Because it binds irreversibly, MAO-B activity recovery after discontinuation requires de novo enzyme synthesis, taking approximately 5–7 days for platelet MAO-B to return to baseline.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral: rapid, Tmax 0.5–1.5 h; bioavailability 4–10% due to extensive first-pass. ODT: 5–8× higher bioavailability via buccal absorption. Patch: ~75% bioavailability, steady state in ~5 days | First-pass generates active metabolites (desmethylselegiline, L-methamphetamine, L-amphetamine). Food increases oral exposure ~3-fold but does not alter t½. ODT and patch bypass first-pass, yielding higher parent drug and fewer metabolites |
| Distribution | Vd ~1,854 L (apparent); protein binding 85–90% (albumin, macroglobulin); rapidly crosses BBB | Highly lipophilic with extensive tissue distribution; concentrates in thalamus, basal ganglia, and midbrain |
| Metabolism | Hepatic via CYP2B6 (major), CYP2A6; N-demethylation → L-methamphetamine; N-depropargylation → desmethylselegiline → L-amphetamine | Metabolite levels with oral dosing are 4–20× higher than parent but remain well below stimulatory thresholds. Desmethylselegiline retains some MAO-B inhibitory activity. Oral contraceptives can increase selegiline exposure 10–20-fold |
| Elimination | Primarily renal as metabolites; t½ ~2 h (single dose), ~10 h (steady state). Oral clearance ~59 L/min (exceeds hepatic blood flow) | Extrahepatic metabolism contributes to clearance. Irreversible MAO-B binding means pharmacodynamic duration far outlasts plasma t½ — clinical effect persists until new enzyme is synthesized |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Application site reaction (EMSAM) | 24% vs 12% placebo | Rotate application site daily; treat persistent reactions with topical corticosteroid or oral antihistamine; leads to discontinuation in ~2% |
| Headache (EMSAM) | 18% vs 17% placebo | Similar to placebo rate; typically mild and self-limiting |
| Insomnia (EMSAM) | 12% vs 7% placebo | Apply patch in the morning; consider dose reduction if persistent and distressing |
| Nausea (oral, with levodopa) | 20% vs 6% placebo | Often attributable to enhanced dopaminergic tone; may resolve with levodopa dose reduction |
| Dizziness/lightheadedness (oral/ODT) | 14% vs 2% placebo | Dose-related; increased risk in patients ≥65 years; advise caution with positional changes |
| Orthostatic hypotension — systolic (ODT) | 21% vs 9% placebo | Greatest risk 2 weeks after dose increase from 1.25 to 2.5 mg; monitor standing BP in elderly |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dry mouth (EMSAM) | 8% vs 6% placebo | Anticholinergic-type effect; manage with oral hygiene, sugar-free lozenges |
| Diarrhea (EMSAM) | 9% vs 7% placebo | Usually self-limiting; ensure adequate hydration |
| Dyskinesia (ODT) | 6% vs 3% placebo | Dopaminergic potentiation; reduce levodopa dose by 10–30% |
| Constipation (ODT) | 4% vs 0% placebo | More common with ODT than oral capsule; increase fiber and fluid intake |
| Hallucinations (oral/ODT) | 4% vs 2% placebo | Visual hallucinations more common in elderly PD patients; dose reduction or discontinuation may be needed |
| Rash (EMSAM) | 4% vs 2% placebo | Higher incidence in patients ≥50 years (4.4% vs 0% placebo); assess for true drug allergy vs local irritation |
| Dyspepsia (EMSAM) | 4% vs 3% placebo | Mild; rarely requires treatment modification |
| Confusion (oral) | 3% vs 1% placebo | Dose-related; more likely in elderly; discontinue if persistent |
| Somnolence (ODT) | 3% vs 1% placebo | Risk increased in patients ≥65; warn about driving and operating machinery |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hypertensive crisis (tyramine reaction) | Rare at approved doses | Minutes to hours after tyramine ingestion | Discontinue selegiline; emergent BP reduction (phentolamine or nifedipine); ED evaluation |
| Serotonin syndrome | Rare (reported in combination with serotonergic drugs) | Hours to days after co-administration with serotonergic agent | Stop all serotonergic agents immediately; supportive care; cyproheptadine may be considered; ICU if severe |
| Suicidal ideation/behavior (EMSAM — young adults) | Increased risk vs placebo in <25 yr | First few weeks of treatment or dose change | Close monitoring, especially weeks 1–4; family education on warning signs; safety planning |
| Falling asleep during daily activities | Rare | Variable; reported up to 1 year after initiation | Discontinue selegiline if episodes occur; counsel against driving until resolved |
| Impulse control disorders (pathological gambling, hypersexuality, compulsive spending) | Uncommon (class effect of dopaminergic agents) | Weeks to months | Dose reduction or discontinuation; direct questioning of patients and caregivers at each visit |
| Withdrawal-emergent hyperpyrexia and confusion (NMS-like) | Very rare | Days after abrupt withdrawal | Do not stop abruptly; taper when discontinuing; supportive care if occurs |
| Mania/hypomania (EMSAM) | Uncommon | First weeks of treatment | Screen for bipolar disorder before initiating EMSAM; discontinue and treat mania if it emerges |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Application site reaction (EMSAM) | 2% vs 0% placebo | Only adverse event causing ≥1% discontinuation at ≥2× placebo rate in EMSAM trials |
| Nausea (oral Eldepryl) | Most common cause | In pre-marketing studies; related to dopaminergic potentiation with levodopa |
| Hallucinations (oral Eldepryl) | Second most common | More frequent in elderly PD patients on multi-drug regimens |
Orthostatic hypotension is one of the most clinically significant adverse effects in the PD population. The systolic orthostatic BP drop rate reached 21% with the ODT at the higher dose vs 9% with placebo. Counsel patients to rise slowly, maintain hydration, and consider timing the dose to reduce overlap with other hypotensive agents. Check orthostatic BP at every visit during the first 8 weeks and after dose adjustments, especially in geriatric patients.
Drug Interactions
Selegiline’s interaction profile is driven by its MAO inhibition. At low oral doses, MAO-B selectivity limits most classic MAOI interactions, but the safety margin narrows with higher doses and with the transdermal formulation, which inhibits both isoforms. All formulations carry contraindications against serotonergic co-prescribing, and the transdermal patch at higher strengths additionally requires dietary tyramine awareness.
Monitoring
-
Blood Pressure
Every visit (first 8 weeks); periodically thereafter
Routine Check supine and standing BP to detect orthostatic hypotension. Particularly important during dose escalation (ODT 1.25 to 2.5 mg, and EMSAM dose increases). Watch for hypertensive events if dose exceeds selective MAO-B range or if patient consumes tyramine-rich foods. -
Mental Status & Mood
Weekly (first 4 weeks); then each visit
Routine Assess for emergent suicidality (EMSAM, especially age <25), hallucinations, psychotic-like behavior, confusion, mania, and impulse control disorders. Include family/caregiver input. -
Hepatic Enzymes
Baseline; as clinically indicated
Trigger-based Transient AST/ALT elevations occur in up to 40% of patients but are typically mild. Repeat if symptoms of hepatotoxicity develop (jaundice, dark urine, RUQ pain). -
Renal Function
Baseline; annually
Routine ODT (Zelapar) is not recommended in severe renal impairment (CrCl <30 mL/min). Check creatinine and estimated GFR at baseline and periodically in elderly PD patients. -
Skin Examination
Periodically
Routine PD patients carry a 2–6-fold increased melanoma risk regardless of medication. Conduct periodic dermatologic screening; for EMSAM, also inspect application sites for persistent skin reactions. -
Somnolence / Sleep Episodes
Every visit
Trigger-based Ask specifically about daytime sleepiness and episodes of sudden sleep onset. Patients may not self-report. If present, assess driving fitness and consider dose reduction or discontinuation. -
Impulse Control Behaviors
Every visit
Trigger-based Screen for new-onset gambling urges, hypersexuality, compulsive spending, or binge eating at each visit. Patients may not recognize behaviors as abnormal; caregiver inquiry is essential.
Contraindications & Cautions
Absolute Contraindications
- Concomitant use with meperidine, tramadol, methadone, pentazocine, or propoxyphene — risk of fatal serotonergic reactions; 14-day washout required after stopping selegiline
- Concomitant use with SSRIs, SNRIs, clomipramine, or imipramine — risk of serotonin syndrome; fluoxetine requires ≥5-week washout
- Concomitant use with other MAOIs (including rasagiline, phenelzine, tranylcypromine, linezolid) — risk of hypertensive crisis
- Concomitant dextromethorphan or St. John’s wort — psychosis, bizarre behavior, serotonin syndrome reported
- Concomitant cyclobenzaprine — structurally similar to TCAs; risk of serotonin syndrome
- Concomitant carbamazepine (EMSAM only) — increases selegiline levels, hypertensive crisis risk
- Pheochromocytoma — risk of catecholamine crisis
- Known hypersensitivity to selegiline or any formulation component
- Age <12 years (EMSAM) — increased risk of hypertensive crisis
Relative Contraindications (Specialist Input Recommended)
- Major psychotic disorder — risk of exacerbating psychosis; antipsychotics may also reduce selegiline efficacy
- Bipolar disorder (EMSAM) — risk of precipitating mania; screen before initiating antidepressant therapy
- Severe hepatic impairment (Child-Pugh >9) for Zelapar — not recommended; no data
- Severe renal impairment or ESRD (CrCl <30 mL/min) for Zelapar — not recommended
- Phenylketonuria (Zelapar ODT only) — contains aspartame/phenylalanine
Use with Caution
- Elderly patients (≥65 years) — increased risk of orthostatic hypotension, somnolence, and hypertension vs younger adults
- Patients requiring surgery — discontinue selegiline at least 10 days before planned surgical procedures
- Patients with pre-existing hypertension — monitor closely; exacerbation possible
- Patients receiving dopamine agonists — additive dopaminergic adverse effects
Antidepressants, including EMSAM, increase the risk of suicidal thinking and behavior in pediatric and young adult patients (aged 18–24) with major depressive disorder and other psychiatric conditions in short-term studies. All patients started on EMSAM should be closely monitored for clinical worsening, suicidality, and unusual changes in behavior, particularly during the initial months of therapy and at times of dose changes. Families and caregivers should be advised to observe the patient closely and communicate any concerns to the prescriber. EMSAM is not approved for use in patients under 12 years of age and is not recommended for patients aged 12 to 17.
Patient Counselling
Purpose of Therapy
For Parkinson disease, explain that selegiline works alongside levodopa to extend its benefit by slowing dopamine breakdown in the brain. It does not cure PD but helps manage motor fluctuations. For depression (EMSAM), explain that the patch delivers medication through the skin to increase brain chemicals that regulate mood, and that full benefit may take several weeks.
How to Take
Oral capsule (Eldepryl): Take 5 mg twice daily with breakfast and lunch. Never take with dinner or at bedtime, as insomnia may result. ODT (Zelapar): Place the tablet on the tongue each morning before breakfast and let it dissolve — do not chew or swallow whole. Avoid food and drink for 5 minutes before and after dosing. Peel the blister pack with dry hands. EMSAM patch: Apply one patch daily to clean, dry, intact skin on the upper torso, upper thigh, or outer upper arm. Rotate sites to reduce irritation. Replace every 24 hours at approximately the same time each day. Keep used and unused patches out of reach of children and pets.
Sources
- Eldepryl (selegiline hydrochloride) capsules — FDA-approved prescribing information. Revised 2008. accessdata.fda.gov Primary source for oral capsule dosing, adverse events in PD, and contraindications.
- Zelapar (selegiline hydrochloride) orally disintegrating tablets — FDA-approved prescribing information. Revised June 2021. accessdata.fda.gov Source for ODT dosing, orthostatic hypotension data, hepatic/renal impairment recommendations, and buccal PK data.
- EMSAM (selegiline transdermal system) — FDA-approved prescribing information. Revised 2017. accessdata.fda.gov Primary source for transdermal dosing in MDD, boxed warning text, tyramine interaction threshold data, and adverse event incidence rates.
- Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease (DATATOP). N Engl J Med. 1993;328(3):176–183. doi:10.1056/NEJM199301213280305 Landmark trial demonstrating selegiline delayed the need for levodopa in early PD by approximately 9 months.
- 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. doi:10.1176/appi.ajp.159.11.1869 Key Phase III trial supporting EMSAM approval for MDD; demonstrated superiority over placebo on HAM-D.
- Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol. 2002;59(12):1937–1943. doi:10.1001/archneur.59.12.1937 Comparator MAO-B inhibitor trial; provides context for selegiline’s relative efficacy in early PD.
- Pringsheim T, Day GS, Smith DB, et al. Practice guideline recommendations summary: treatment of motor symptoms of Parkinson disease. Neurology. 2024;103(6):e209739. doi:10.1212/WNL.0000000000209739 AAN guideline update addressing MAO-B inhibitor use as adjunctive therapy in PD with motor fluctuations.
- American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd edition. Am J Psychiatry. 2010;167(10 Suppl):1–152. doi:10.1176/appi.books.9780890423387.654001 Recommends MAOIs including transdermal selegiline for treatment-resistant and atypical depression.
- Youdim MBH, Bakhle YS. Monoamine oxidase: isoforms and inhibitors in Parkinson’s disease and depressive illness. Br J Pharmacol. 2006;147(Suppl 1):S287–S296. doi:10.1038/sj.bjp.0706464 Comprehensive review of MAO-A vs MAO-B isoform differences and the mechanistic rationale for dose-dependent selectivity of selegiline.
- Szoko E, Tabi T, Riederer P, et al. Pharmacological aspects of the neuroprotective effects of irreversible MAO-B inhibitors, selegiline and rasagiline, in Parkinson’s disease. J Neural Transm. 2018;125(11):1735–1749. doi:10.1007/s00702-018-1853-9 Explores neuroprotective mechanisms beyond MAO-B inhibition, including antiapoptotic effects and TAAR1 agonism.
- Mahmood I. Clinical pharmacokinetics and pharmacodynamics of selegiline: an update. Clin Pharmacokinet. 1997;33(2):91–102. doi:10.2165/00003088-199733020-00002 Definitive PK review providing bioavailability (10%), Vd (1,854 L), clearance data, and food-effect analysis for oral selegiline.
- Azzaro AJ, Ziemniak J, Kemper E, et al. Pharmacokinetics and absolute bioavailability of selegiline following treatment with the selegiline transdermal system. J Clin Pharmacol. 2007;47(10):1256–1267. doi:10.1177/0091270007304779 Compares transdermal vs oral PK; demonstrates ~75% bioavailability and reduced metabolite formation with patch delivery.
- Montastruc JL, Chaumerliac C, Desboeuf K, et al. Adverse drug reactions to selegiline: a review of the French pharmacovigilance database. Clin Neuropharmacol. 2000;23(5):271–275. doi:10.1097/00002826-200009000-00006 Pharmacovigilance analysis showing higher rates of cardiovascular and psychiatric ADRs with selegiline vs other antiparkinsonian drugs.