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Selegiline (Monograph)

Brand names: Eldepryl, Zelapar
Drug class: Monoamine Oxidase B Inhibitors
- Antiparkinsonian Agents
- Monoamine Oxidase Inhibitors
- MAO Inhibitors
VA class: CN500
Chemical name: (R)-N,α-Dimethyl-N-2-propynyl-benzeneethanamine hydrochloride
Molecular formula: C13H17N•ClH
CAS number: 14611-52-0

Medically reviewed by Drugs.com on Apr 29, 2024. Written by ASHP.

Introduction

Selective irreversible MAO-B inhibitor.1 2 3 144 158

Parkinsonian Syndrome

Used as adjunctive therapy for symptomatic treatment of parkinsonian syndrome (e.g., parkinsonism, Parkinson disease [paralysis agitans]) in patients who exhibit a deteriorating response to levodopa/carbidopa; designated an orphan drug by FDA for this condition.1 2 4 5 6 7 8 34 35 36 37 38 39 40 65 66 85 92 93 144 Appears to be most beneficial when used during the early stages of the “wearing off” effect.6 7 36 38 49 Especially useful in improving “end-of-dose” motor fluctuations.5 6 7 49 51 85

Has been used as monotherapy in patients with newly diagnosed parkinsonian syndrome† [off-label].5 7 8 37 53 54 55 56 73 84 85 93 130 Because selegiline is well tolerated and possibly neuroprotective (i.e., reduces the rate of progression of parkinsonian syndrome3 5 8 53 54 55 56 57 58 59 60 130 ), some clinicians initiate therapy with selegiline in such patients, reserving levodopa or another agent (i.e., dopamine agonist) until manifestations become severe enough to warrant more aggressive therapy.8 11 57 65 122 130 However, the manufacturers state that there is no evidence from controlled studies indicating that selegiline provides benefit in the absence of concurrent levodopa therapy.1 2

Alzheimer’s Disease

Has been used with equivocal results for the palliative treatment of mild to moderate dementia of the Alzheimer’s type† [off-label] (Alzheimer’s disease, presenile or senile dementia).61 62 63 104 105 106 107 127 128

Selegiline Dosage and Administration

Administration

Administer orally.1 2 144

Oral Administration

Administer orally as conventional tablets, capsules, or orally disintegrating tablets.1 2 144

Administer conventional tablets and capsules in 2 equally divided doses daily with breakfast and lunch.1 2 8 11

Administer orally disintegrating tablets (Zelapar) once daily in the morning before breakfast.144 Avoid foods or liquids for 5 minutes prior to and after administration.144 Do not remove tablets from blister pack until just prior to administration.144 With dry hands, peel backing off 1 or 2 blister packs (depending on dosage); gently remove tablet(s) and place on tongue where dissolution occurs in seconds.144 (See Absorption under Pharmacokinetics.)

Dosage

Available as selegiline hydrochloride; dosage expressed in terms of the salt.1 144

Adults

Parkinsonian Syndrome
Adjunctive Therapy with Levodopa
Oral

Conventional tablets and capsules: Usual dosage 5 mg twice daily.1 2 5 6 11 Some clinicians suggest initial dosage of 2.5 mg daily;122 may increase gradually up to 5 mg twice daily.8 Dosages >10 mg daily do not provide additional benefit and may increase risk of adverse effects; generally avoid such dosages.1 2

Orally disintegrating tablets: Initially, 1.25 mg once daily for ≥6 weeks.144 If desired response not achieved by 6 weeks, may increase to 2.5 mg once daily, if tolerated.144 Dosages >2.5 mg daily do not provide additional benefit and may increase risk of adverse effects; generally avoid such dosages.144

If dyskinesia develops or is exacerbated during therapy, may reduce dosage of concomitant levodopa.1 2 144 (See Dyskinesia under Cautions.) Manufacturers of conventional oral preparations of selegiline state that dosage reduction of levodopa/carbidopa (usually by 10–30%) may be attempted after 2–3 days of selegiline therapy with further reduction possible during continued therapy.1 2

Special Populations

Hepatic Impairment

Conventional oral preparations: Manufacturers make no specific dosage recommendations in patients with hepatic impairment.1 2

Orally disintegrating tablets: In patients with mild to moderate hepatic impairment (Child-Pugh score 5–9), reduce dosage to 1.25 mg daily (depending on clinical response); use not recommended in patients with severe hepatic impairment (Child-Pugh score >9).144

Renal Impairment

Conventional oral preparations: Manufacturers make no specific dosage recommendations in patients with renal impairment.1 2

Orally disintegrating tablets: No dosage adjustments required in patients with mild to moderate renal impairment (Clcr 30–89 mL/minute); individualize dosage.144 Use not recommended in patients with severe renal impairment and those with end-stage renal disease (Clcr <30 mL/minute).144

Geriatric Patients

No specific dosage recommendations.1 144

Detailed Selegiline dosage information

Cautions for Selegiline

Contraindications

Warnings/Precautions

Warnings

Risks Associated with Nonselective MAO Inhibition

Risk of serious hypertensive reactions associated with nonselective MAO inhibition.1 2 144 Selectivity for MAO-B is relative.1 2 3 At recommended dosages, selegiline inhibits cerebral MAO-B while having little effect on MAO-A in the GI tract and liver.1 2 4 5 22 32 84 At higher dosages, selectivity for MAO-B usually diminishes and the drug will inhibit MAO-B and MAO-A.1 2 4 5 22 32 144

Hypertensive crises following ingestion of foods containing large amounts of tyramine (i.e., cheese reaction) have occurred in patients receiving nonselective MAO inhibitors.123 Hypertensive reactions reported rarely in patients receiving recommended dosages of selegiline hydrochloride with tyramine-rich foods or sympathomimetic drugs;1 as dosage is increased beyond recommended dosages, the likelihood of hypertensive reactions increases.1 2 5 9 10 11 12 113 144 (See Interactions.)

Use selegiline with caution.1 Do not exceed recommended dosages.1 (See Dosage under Dosage and Administration.) The exact dosage at which selegiline hydrochloride becomes a nonselective inhibitor of MAO not known, but may be 30–40 mg daily (with conventional oral preparations) or 5 mg daily (with orally disintegrating tablets).1 2 144 (See Advice to Patients.)

Because of the complexity of the MAO enzyme system, observe patients closely for atypical responses.1

Serotonin Syndrome

Concomitant use of highly serotonergic drugs (e.g., SSRIs, tricyclic antidepressants) and MAO inhibitors, including selegiline, is potentially hazardous and may result in serotonin syndrome.1 2 13 16 17 97 99 100 101 112 Manifestations may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1 126 131 133 Generally avoid concomitant use.1 2 (See Interactions.)

General Precautions

Dyskinesia

Selegiline may exacerbate levodopa-associated adverse effects (e.g., dyskinesia1 2 5 49 50 64 66 68 144 ), presumably by increasing dopaminergic activity; effects generally can be mitigated by reducing levodopa dosage.1 2 5 68 144 (See Adjunctive Therapy with Levodopa under Dosage and Administration.)

Sudden Sleep Episodes

Episodes of falling asleep while engaged in activities of daily living (e.g., driving) reported with dopaminergic drugs, sometimes resulting in accidents.144

Some patients perceived no warning signs (e.g., excessive drowsiness) and believed they were alert immediately prior to the event.144

Generally discontinue therapy if a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating).144 If the drug is continued, advise patients not to drive and to avoid other potentially dangerous activities.144

Hypotension

Orthostatic hypotension reported; risk appears to be increased after dosage increases.144 Incidence higher in geriatric patients.144

Melanoma

Epidemiologic studies indicate patients with Parkinson disease have a twofold to approximately sixfold greater risk of developing melanoma than the general population.1 2 Unclear whether increased risk is due to Parkinson disease or other factors (e.g., drugs used to treat the disease).1 2

Monitor for melanoma on a frequent and regular basis.1 2 Manufacturers recommend periodic skin examinations performed by qualified clinicians (e.g., dermatologists).1 2

Intense Urges

Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including selegiline).1 2 144 Although causal relationship not established, urges stopped in some cases when dosage was reduced or drug was discontinued.1 2 144

Consider reducing dosage or discontinuing selegiline if a patient develops such urges.1 2 144

Neuroleptic Malignant Syndrome

Symptoms resembling neuroleptic malignant syndrome (NMS) (e.g., muscular rigidity, autonomic instability, altered consciousness) reported with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.144 (See Advice to Patients.)

Irritation of Buccal Mucosa

Increased frequency of mild oropharyngeal abnormality (e.g., swallowing pain, mouth pain, discrete areas of focal reddening, multiple foci of reddening, edema, and/or ulceration) reported in patients receiving selegiline orally disintegrating tablets.144

Phenylketonuria

Warn individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine that selegiline orally disintegrating tablets (Zelapar) contain aspartame (NutraSweet), which is metabolized in the GI tract to provide about 1.25 mg phenylalanine per tablet.144 145 146 147 148 149

Renal Effects

Small increases in Scr and BUN reported in patients receiving high dosages of selegiline orally disintegrating tablets (10 mg daily).144

Specific Populations

Pregnancy

Category C.1 No adequate and well-controlled studies in pregnant women; developmental toxicity observed in animal studies.1 2 144

Lactation

Not known whether selegiline is distributed into milk.1 2 Use caution.144 Some manufacturers state to give consideration to discontinuing the use of all but absolutely essential drug therapy in nursing women.1 2

Pediatric Use

Safety and efficacy not established.1 2 144

Geriatric Use

Safety and efficacy in geriatric patients not studied specifically to date; however, parkinsonian syndrome, for which safety and efficacy have been established, occurs principally in patients >50 years of age.1 2 4 5 6 7 8 34 35 36 37 38 39 40 53 54 55 56

Greater frequency of certain adverse effects (e.g., hypertension, orthostatic hypotension) reported in geriatric patients ≥65 years of age compared with younger patients.144

Common Adverse Effects

Conventional tablets and capsules: Nausea;1 2 5 6 39 50 66 dizziness, lightheadedness, or fainting; abdominal pain; hallucinations; dry mouth; vivid dreams; dyskinesias; headache.1

Orally disintegrating tablets: Constipation, skin disorders, vomiting, dizziness, dyskinesia, insomnia, dyspnea, myalgia, rash.144

Many of the adverse effects in patients receiving selegiline plus levodopa result from increased dopaminergic activity and can be mitigated by reducing levodopa dosage; these effects include exacerbation of dyskinesias, confusion, and hallucinations.1 2 5 49 50 64 66 67 68

Drug Interactions

Metabolized by CYP2B6, CYP3A4, and possibly CYP2A6 (to a lesser extent).144 Does not inhibit CYP enzymes; little or no potential for inducing CYP1A2 and CYP3A4/5.144

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Pharmacokinetic interactions unlikely.144

CYP3A4 inducers: Use concomitantly with caution.144

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)

Specific studies not conducted to evaluate effect on pharmacokinetics of selegiline144

Use concomitantly with caution144

Antidepressants (e.g., SNRIs, SSRIs, tetracyclics, tricyclics, triazolopyridine derivatives)

Potential for serious, possibly fatal serotonin syndrome1 2 13 16 17 97 99 100 101 112 122 126 131 144

Generally avoid concomitant use1 2 17 99 100 101 144

Allow ≥2 weeks to elapse between discontinuance of selegiline and initiation of antidepressant1 2 17 99 100 101 144

Allow ≥5 weeks to elapse between discontinuance of fluoxetine and initiation of selegiline; consider a longer interval after long-term or high-dosage fluoxetine therapy1 2 17 144

Allow ≥2 weeks to elapse between discontinuance of fluvoxamine, paroxetine, or sertraline and initiation of selegiline99 100 101

Allow ≥2 weeks to elapse between discontinuance of a tricyclic antidepressant and initiation of selegiline102 103

Antipsychotic agents (i.e., dopamine antagonists)

Possible reduced efficacy of selegiline144

Cyclobenzaprine

Potential for serious, possibly fatal serotonin syndrome144

Concomitant use contraindicated144

Dextromethorphan

Possible psychosis and bizarre behavior144

Concomitant use contraindicated144

Foods, tyramine-containing

Hypertensive reactions reported rarely1

Nonselective inhibition of MAO increases risk of hypertensive reactions; selectivity for MAO typically decreases as dosage of selegiline is increased above recommended dosages (>10 mg daily with conventional oral preparations or >2.5 mg daily with orally disintegrating tablets)1 2 5 9 10 11 12 113 144

Do not exceed recommended dosages of selegiline1 2 144

Exercise caution regardless of the dosage;1 avoid foods and beverages with high tyramine content5 9 10 12 32

Safe use of selegiline orally disintegrating tablets at dosages >2.5 mg daily without dietary tyramine restrictions not established144

Consult specialized references on food constituents or a dietician for specific information on the tyramine content of foods and beverages122

Itraconazole

No changes observed in pharmacokinetics of selegiline144

Levodopa

Potential for exacerbation of levodopa-associated adverse effects in some patients, presumably secondary to increased dopaminergic activity1 2 5 68 144

Reduction of levodopa dosage may mitigate adverse effects1 2 5 68 144

Combination used to therapeutic advantage1 2 36 38 39 40 53 54 55 56 66 73

MAO inhibitors (nonselective or selective)

May increase risk of nonselective MAO inhibition, possibly resulting in hypertensive crisis144

Concomitant use contraindicated144

Allow ≥14 days to elapse between discontinuance of selegiline and initiation of other MAO inhibitors144

Metoclopramide

Possible reduced efficacy of selegiline144

Nafcillin

Specific studies not conducted to evaluate effect on pharmacokinetics of selegiline144

Use concomitantly with caution144

Opiate agonists (e.g., meperidine, methadone, propoxyphene [no longer commercially available in US], tramadol)

Potential for serious, possibly fatal serotonin syndrome1 2 5 19 20 112 118 144

Concomitant use with meperidine, methadone, and tramadol contraindicated; allow ≥14 days to elapse between discontinuance of selegiline and initiation of opiate agonist1 2 5 19 21 144

Consider discontinuing selegiline 2 weeks prior to scheduled surgery if postoperative meperidine analgesia is possible112

Rifampin

Specific studies not conducted to evaluate effect on pharmacokinetics of selegiline144

Use concomitantly with caution144

St. John's wort (Hypericum perforatum)

Potential for serious, possibly fatal serotonin syndrome144

Concomitant use contraindicated144

Sympathomimetic agents (e.g., ephedrine)

Hypertensive crisis reported in at least one patient receiving selegiline hydrochloride 10 mg daily (as a conventional oral preparation) and ephedrine1 2
Selegiline drug interactions (more detail)

Selegiline Pharmacokinetics

Absorption

Bioavailability

Conventional tablets and capsules: Rapidly absorbed following oral administration; peak plasma selegiline concentrations achieved within 0.5–0.9 hours in fasting individuals.86 87 108 110 Undergoes extensive first-pass metabolism in gut wall and liver.1 32 108 Following single oral 10-mg capsule dose, peak plasma concentrations of the first-pass metabolites (l-desmethylselegiline, l-methamphetamine, and l-amphetamine) are 3- to 20-fold higher than the peak plasma concentrations of selegiline.1 108 110 At steady state, peak plasma selegiline and metabolite concentrations are increased 2.6- to 4-fold and 1.5- to 2-fold, respectively, compared with values following a single dose.1 108 Oral bioavailability of 10% reported for selegiline hydrochloride conventional tablets.108

Orally disintegrating tablets: Absorbed more rapidly than conventional tablet formulation; mean peak plasma concentrations achieved within 10–15 minutes following buccal administration of a single 1.25- or 2.5-mg dose.144 155 Peak plasma concentrations and AUC are dose proportional over dosage range of 1.25–10 mg daily and steady state is achieved after 8 days.144 156 Undergoes pregastric absorption through buccal mucosa and substantially bypasses first-pass metabolism, resulting in higher plasma concentrations of selegiline and lower concentrations of metabolites than those achieved with conventional oral formulations.144 155 156 Relative bioavailability of selegiline from orally disintegrating tablets is greater than that from conventional formulations.144 150

Food

Conventional tablets and capsules: Food increases oral bioavailability of selegiline 3- to 5-fold but does not appear to affect the pharmacokinetics of the first-pass metabolites.1 108

Orally disintegrating tablets: Presence of food in the GI tract decreases AUC and peak plasma concentrations to approximately 60% of those seen when the drug is administered in the fasted state.144 (See Dosage and Administration: Administration.)

Special Populations

Following administration of orally disintegrating tablets in patients with mild to moderate hepatic impairment (Child-Pugh 5–9), peak plasma concentrations and systemic exposure of selegiline and desmethylselegiline were increased.144 In patients with severe hepatic impairment (Child-Pugh >9), these pharmacokinetics parameters were considerably increased (by threefold to fourfold).144

Following administration of orally disintegrating tablets in patients with renal impairment, including those with end-stage renal disease, peak plasma concentrations and systemic exposure of selegiline and desmethylselegiline were not substantially altered; however, exposure to the methamphetamine and amphetamine metabolites were increased.144

Following administration of a single 10-mg dose (as conventional tablets) in a limited number of adults ≥60 years of age, systemic exposure was twice that reported in adults 18–30 years of age.1

Distribution

Extent

Selegiline and its metabolites are widely distributed into body tissues.1 2 5 27 28 29 30 31 32 44

Selegiline and its metabolites cross the blood-brain barrier1 2 5 27 28 29 30 31 32 44 with highest accumulation in thalamus, basal ganglia, mesencephalon, and cingulate gyrus.27 28

Selegiline and/or its metabolites also detected in the liver29 and hair.88

Plasma Protein Binding

Selegiline and/or its metabolites: Up to 94%.5 31 32 44

Elimination

Metabolism

Extensively metabolized, principally in the gut wall and liver, to l-desmethylselegiline and l-methylamphetamine (CYP-mediated) and then to l-amphetamine.1 32 108 Metabolized by CYP2B6, CYP3A4, and possibly CYP2A6 to a lesser extent.144 The amphetamine metabolites may be hydroxylated and then conjugated with glucuronic acid.5 32 88 108

l-Desmethylselegiline is an irreversible inhibitor of MAO-B,1 32 44 45 46 47 110 but its contribution to MAO-B inhibition during selegiline therapy may be only minor.110 The levorotatory amphetamine isomers are less potent CNS stimulants than the racemic or dextrorotatory isomers.5 26 44

When administered as the orally disintegrating tablet, substantially bypasses first-pass metabolism.144 155 156

Elimination Route

Excreted principally in urine as conjugated and unconjugated metabolites1 5 12 26 27 28 29 30 31 32 44 (20–63% as l-methamphetamine, 9–26% as l-amphetamine, and 1% as l-desmethylselegiline).5 12 31 44

Urinary excretion of amphetamines is enhanced in acidic urine.5 31 44

Half-life

Selegiline: Approximately 1.2–2 hours following single oral doses of 10 mg (as conventional oral preparations) or 1.25 mg (as orally disintegrating tablets),1 87 108 144 and about 10 hours at steady state.1 108 144

Metabolites: 2 hours (l-desmethylselegiline), 20.5 hours (l-methamphetamine), and 17.7 hours (l-amphetamine).2 44

Stability

Storage

Oral

Conventional Tablets and Capsules

20–25°C.1 2

Orally Disintegrating Tablets

25°C (may be exposed to 15–30°C).144 Use within 3 months of opening pouch and immediately upon opening individual blister.144 Store blister tablets in pouch.144

Actions

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Selegiline Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

5 mg*

Eldepryl

Somerset

Selegiline Hydrochloride Capsules

Tablets

5 mg*

Selegiline Hydrochloride Tablets

Tablets, orally disintegrating

1.25 mg

Zelapar

Valeant

AHFS DI Essentials™. © Copyright 2024, Selected Revisions May 7, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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