VA Class:CN500

VA Class:CN602

AHFS Class:

• Monoamine Oxidase B Inhibitors 28:36.32

Generic Name(s):

• Selegiline Hydrochloride

Chemical Name:

• ( R )- N ,α-Dimethyl- N -2-propynyl-benzeneethanamine hydrochloride

Molecular Formula:

• C₁₃H₁₇N•ClH

Selegiline hydrochloride, a propargyl amphetamine derivative, is a selective and irreversible inhibitor of monoamine oxidase-B (MAO-B).1,2,3,144,158

Parkinsonian Syndrome

Selegiline hydrochloride is used as adjunctive therapy for the symptomatic treatment of parkinsonian syndrome (e.g., parkinsonism, Parkinson disease [paralysis agitans]) in patients who exhibit a deteriorating response to levodopa/carbidopa therapy (see Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16); selegiline has been designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.1,2,4,5,6,7,8,34,35,36,37,38,39,40,65,66,85,92,93,144

Levodopa (in combination with carbidopa) is considered the most effective drug for relieving motor manifestations of parkinsonian syndrome.8,11,65,66,85,89,157,160 However, the effectiveness of levodopa decreases substantially over time, and most patients develop complications such as motor fluctuations and dyskinesias (drug-induced involuntary movements) with long-term use.1,2,6,8,11,53,57,65,66,89,157,160 Several types of motor fluctuations, including return of parkinsonian manifestations toward the end of an interdose period (“ wearing off” effect), sudden loss of effectiveness that may last from 1 minute to an hour followed by an equally sudden return of effectiveness (“on-off” phenomena), and sudden hypotonic freezing episodes, may occur in some patients during long-term levodopa therapy.8,65,66,85 When used in conjunction with levodopa/carbidopa, selegiline may provide additional therapeutic benefit in patients who currently are maintained on optimal dosages of levodopa, patients who are beginning to develop tolerance to levodopa, and patients who are experiencing “end-of-dose” failure on levodopa therapy.1,2,5,6,7,11,36,38,49,50,51,52,85,122,144

In clinical studies used to establish efficacy of selegiline, patients were eligible for inclusion if they had a history of idiopathic parkinsonian syndrome (i.e., syndrome was not induced by drugs, trauma, or a tumor or associated with some other neurologic disorder).48 In double-blind controlled studies in patients receiving optimum therapy for parkinsonian syndrome that included levodopa/carbidopa, addition of selegiline (as conventional oral preparations) was more effective than placebo in the following outcome measures: decrease in the amount of “off” time, improvement in patient self-rating of therapeutic success, and reduction in levodopa dosage.1,2,36,38,39,40,53,55,56,66,73 In these studies, selegiline produced beneficial effects on other outcome measures including reduced “end-of-dose” akinesia, tremor, and sialorrhea; improved speech and dressing ability; and overall disability as assessed by walking and symptomatic improvement.1,2,36,38,39,40,53,55,56,66,73

Efficacy of selegiline orally disintegrating tablets has been established in a 12-week randomized, placebo-controlled study in patients with idiopathic Parkinson disease (mean disease duration of 7 years) who were experiencing mild to moderate motor fluctuations and a minimum of 3 hours of “off” time per day while receiving levodopa therapy.144,152 Selegiline hydrochloride (1.25 mg daily for the first 6 weeks followed by 2.5 mg daily for the remainder of the study as orally disintegrating tablets) was more effective than placebo in reducing daily “off” time from baseline to the end of treatment (mean reduction of 13 versus 5%); “off” time was reduced by an average of 2.2 hours with selegiline compared with 0.6 hours with placebo.144,152 Selegiline also improved dyskinesia-free “on” time and parkinsonian manifestations as assessed by the Unified Parkinson's Disease Rating scale (UPDRS) and the Clinical Global Impression (CGI) and Patient Global Impression (PGI) scales.152 In another placebo-controlled study of similar design, selegiline orally disintegrating tablets did not substantially improve “off” time compared with placebo; however, there was a large placebo effect in this study and the overall response to selegiline was considered to be similar in both studies.153,154 An open-label extension study, which included patients from the 2 placebo-controlled studies, was conducted to evaluate long-term efficacy of selegiline hydrochloride orally disintegrating tablets (2.5 mg daily).150 Patients who received at least 40 weeks of selegiline therapy in the extension study had a mean reduction in “off” time of 8.1%; however, there was a large discontinuance rate, with only 35% of the patients completing the study.150

Selegiline therapy appears to be most beneficial when used during the early stages of the “wearing off” effect; patients exhibiting severe “on-off” phenomena during levodopa therapy and patients with advanced parkinsonian syndrome are less likely to benefit from selegiline therapy.6,7,36,38,49 In clinical studies, addition of selegiline to levodopa therapy was especially useful in improving “end-of-dose” motor fluctuations.5,6,7,49,51,85 Selegiline improved “end-of-dose” fluctuations in 50-63% of patients and early morning akinesia in 56% of patients treated in several studies.5,6 In clinical studies, selegiline improved mild “on-off” disabilities and freezing; however, selegiline is not useful in the management of severe “on-off” oscillations.5,6,7,38,49,50,51,52,124 In patients responding to selegiline therapy, resting tremor and facial expression are relieved more frequently than rigidity.5,50 Sustained improvement may last up to 4 years;36,38 however, some patients experience a reduction in benefit after about 8 months.5,7,49,64 In patients receiving optimum antiparkinsonian therapy, addition of selegiline has allowed for average reductions in levodopa dosage of about 10-30%.1,2,5,6,7,34,38,40,144

The effect of selegiline on survival in patients with parkinsonian syndrome has not been determined.39,51,89,90,91,93,95,96,125 In one retrospective study, survival time from initiation of levodopa until death averaged 12 or 10.75 years in patients receiving selegiline and those not receiving the drug, respectively.39,51 However, in a prospective, randomized, open long-term study in patients with early parkinsonian syndrome (i.e., symptomatic patients in need of dopaminergic therapy but not receiving such therapy), 28% of patients receiving selegiline in combination with levodopa or 18% of patients receiving levodopa alone died over a mean 5.6-year follow-up period.89,90,91,93 While disability scores at 4 years' follow-up were similar in both groups, the largest difference in mortality rates between the two groups was in deaths caused by parkinsonian syndrome.89,90 In another retrospective review of a large US study in patients with early parkinsonian syndrome who received selegiline, the death rate in these patients was similar to that of age- and gender-matched US population without parkinsonian syndrome.125

Whether adjunctive therapy with selegiline is more effective than other adjunctive agents (e.g., dopamine agonists, anticholinergic agents, amantadine) in parkinsonian patients receiving levodopa has not been determined.7,57 Therapy with levodopa, selegiline, and a dopamine agonist has been used successfully in some patients; however, efficacy of this combination compared with therapy with levodopa alone has not been established.40,49,51

Addition of selegiline to a therapeutic regimen in patients in whom parkinsonian syndrome has been induced by drugs, trauma, or a tumor, or is associated with some other neurologic disorder has not been systematically evaluated to date.48 Selegiline has been used in a limited number of patients with neuroleptic-induced extrapyramidal manifestations†; the drug may be useful in patients who do not respond to anticholinergic agents.74

Selegiline also has been used as monotherapy in patients with newly diagnosed parkinsonian syndrome†;5,7,8,37,53,54,55,56,130 however, the manufacturers state that there is no evidence from controlled studies indicating that the drug provides benefit in the absence of concurrent levodopa therapy.1,2 144 Although levodopa is considered the most effective drug for controlling motor symptoms in patients with idiopathic parkinsonian syndrome, some clinicians initiate therapy with other dopaminergic agents (e.g., MAO-B inhibitors, amantadine, dopamine agonists) first in order to delay introduction of levodopa and avoid the long-term complications of therapy.8,11,37,57,65,130,157 Results from placebo-controlled studies, using delay in onset of manifestations requiring levodopa therapy as the end point, indicate that selegiline delays the onset of disability in patients with early (i.e., less than 5 years) untreated idiopathic parkinsonian syndrome.5,8,53,54,55,56,57 In one large study, delay to initiation of levodopa therapy averaged 2 or 1.25 years in patients receiving selegiline or placebo, respectively.8,53,54,119,120,121 However, the initial benefit of selegiline therapy may not be sustained.119,120,121,122,125 Although it has been suggested that selegiline is “neuroprotective” (i.e., reduces the rate of progression of parkinsonian syndrome),3,5,8,53,54,55,56,57,58,59,60,130 whether the delay in the development of motor disability in patients receiving the drug is secondary to a neuroprotective effect on residual dopamine neurons or to symptomatic effects that mask detection of the underlying disability has not been determined.5,8,11,53,54,55,56,57,58,59,60,130 Because selegiline is well tolerated and possibly neuroprotective, some clinicians initiate therapy with selegiline in newly diagnosed parkinsonian patients, reserving levodopa or another agent (i.e., a dopamine agonist) until manifestations become severe enough to warrant more aggressive therapy.8,11,57,65,122,130

Although it has been suggested that selegiline therapy may provide antidepressant benefit in patients with parkinsonian syndrome and associated depressive manifestations,115,116 dosages required for antidepressant activity may exceed those required for antiparkinsonian activity,115 and such dosages are associated with an increased risk of adverse effects.115,117 In addition, current evidence is too limited to recommend any specific antidepressant for use in patients with parkinsonian syndrome and associated depression.117,122

Alzheimer's Disease

Selegiline has been used with equivocal results for the palliative treatment of mild to moderate dementia of the Alzheimer's type† (Alzheimer's disease, presenile or senile dementia).61,62,63,104,105,106,107,127,128 In the largest double-blind, controlled study to date comparing selegiline, vitamin E, combined therapy with both drugs, and placebo in patients with moderately severe dementia of the Alzheimer's type,104 selegiline or vitamin E was more effective than combined therapy, and all therapies were more effective than placebo, in decreasing the rate of functional decline (e.g., delaying the onset of poor outcome such as death, need for institutionalization, loss of ability to perform basic living tasks, deterioration in clinical dementia rating) when analysis of the results was adjusted for differences in baseline values for the study groups, but not for unadjusted data.104,105,106,107 However, there was no evidence of improvement in function compared with baseline, and all groups showed similar rates of cognitive decline over 2 years.104,105,106,107 In addition, methodologic concerns about this study and the associated conclusions have been raised.105,106,107,127,128 Although several other smaller studies showed some evidence of benefit with selegiline therapy,61,62,107 some experts state that evidence of clinical benefit for the drug in patients with dementia of the Alzheimer's type currently is inconclusive.106 Other experts, however, state that despite limitations of current evidence, a trial with selegiline therapy may be considered for Alzheimer's patients with mild to moderate impairment, although comparable evidence of efficacy with vitamin E and a more favorable toxicity profile of the vitamin may make this agent preferable to selegiline.107,127,129 Additional study and experience are needed to define more precisely the role of selegiline in the management of Alzheimer's disease.104,105,106,107,122,129

Administration

Selegiline hydrochloride is administered orally as conventional tablets, capsules, or orally disintegrating tablets for the management of parkinsonian syndrome.1,2,144

Conventional oral preparations of the drug are administered in 2 equally divided doses daily with breakfast and lunch.1,2,8,11

Selegiline orally disintegrating tablets (Zelapar^®) should be administered once daily in the morning before breakfast.144 Patients should avoid ingesting any foods or liquids for 5 minutes prior to and after administration of the tablets.144 The orally disintegrating tablets should not be removed from their original packaging (blister packs) until just prior to administration.144 With dry hands, the backing of 1 or 2 blisters (depending on dosage) should be peeled open; the tablet(s) should be gently removed and placed immediately on the tongue where dissolution occurs in seconds.144 (See Pharmacokinetics: Absorption.)

Dosage

Dosage of selegiline hydrochloride is expressed in terms of the salt.1,144

Parkinsonian Syndrome

For adjunctive therapy to levodopa/carbidopa in the symptomatic management of parkinsonian syndrome, the usual adult dosage of selegiline hydrochloride (as conventional tablets or capsules) is 5 mg twice daily.1,2,5,6,11 Some clinicians suggest an initial selegiline hydrochloride dosage of 2.5 mg daily;122 dosage may be increased gradually to a maximum of 5 mg twice daily.8 The manufacturers state that dosages exceeding 10 mg daily (as conventional tablets or capsules) generally should be avoided because they do not provide additional benefit and may increase the risk of adverse effects.1,2

The recommended initial adult dosage of selegiline hydrochloride (as orally disintegrating tablets) is 1.25 mg once daily for at least 6 weeks.144 If a desired response is not achieved by 6 weeks, dosage may be increased to 2.5 mg once daily, if tolerated.144 The manufacturer states that dosages exceeding 2.5 mg daily (as orally disintegrating tablets) generally should be avoided because they do not provide additional benefit and may increase the risk of adverse effects.144

Because selegiline may potentiate the adverse dopaminergic effects of levodopa and cause or exacerbate dyskinesia, dosage of levodopa may be reduced during concomitant therapy to mitigate this effect.1,2,144 The 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; further reduction in the dosage of levodopa/carbidopa may be possible during continued selegiline therapy.1,2

Special Populations

The manufacturers of conventional oral preparations of selegiline make no specific dosage recommendations for patients with hepatic or renal impairment.1,2

The manufacturer of selegiline hydrochloride orally disintegrating tablets states that in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), dosage should be reduced to 1.25 mg daily depending on clinical response; use of the drug is not recommended in patients with severe hepatic impairment (Child-Pugh score greater than 9).144

The manufacturer of selegiline orally disintegrating tablets states that no dosage adjustment is required in patients with mild to moderate renal impairment (creatinine clearance of 30-89 mL/minute); however, dosage should be individualized based on clinical response.144 Use of the drug is not recommended in patients with severe renal impairment and those with end-stage renal impairment (creatinine clearance less than 30 mL/minute).144

In therapeutic dosages, selegiline hydrochloride generally is well tolerated.5,39,40,49,50,53,54,55,64,66,67 Many of the adverse effects in patients receiving selegiline plus levodopa result from increased dopaminergic activity and can be mitigated by reducing levodopa dosa these effects include exacerbation of dyskinesias, confusion, and hallucinations.1,2,5,49,50,64,66,67,68 Nausea also has been reported commonly in patients receiving selegiline and levodopa.1,2,5,6,39,50,66 Overall, the type and severity of adverse effects produced by selegiline plus levodopa appear to be similar to those produced by levodopa.1,2,5 Transient episodes of insomnia, headache, dizziness, nausea, and euphoria have occurred in patients receiving selegiline monotherapy; in one placebo-controlled study, only insomnia occurred more frequently in patients receiving selegiline than in those receiving placebo.55

Because only a limited number of patients have been evaluated in controlled, prospective studies, the manufacturers state that the overall incidence as well as the importance and severity of adverse effects in patients receiving selegiline have not been established.1,2 However, one index of relative importance is whether discontinuance of selegiline therapy was required.1,2 In the limited clinical trials used to establish efficacy of selegiline (as conventional tablets and capsules), discontinuance of the drug was required in some patients, principally because of (in order of descending frequency) nausea, hallucinations, confusion, depression, loss of balance, insomnia, orthostatic hypotension, increased akinetic involuntary movements, agitation, arrhythmia, bradykinesia, chorea, delusions, hypertension, new or exacerbated angina pectoris, and syncope.1,2 Other events requiring discontinuance of selegiline (each reported at least once) include ankle edema, anxiety, burning lips/mouth, constipation, drowsiness/lethargy, dystonia, excess perspiration, increased freezing episodes, GI bleeding, hair loss, increased tremor, nervousness, weakness, and weight loss.1,2 Because the full spectrum of possible responses, including potential adverse effects, cannot be ascertained from the limited premarketing experience with selegiline, patients should be observed closely for atypical responses and the decision to use selegiline should weigh the limited nature of current evidence with the drug.1,2

In clinical studies of selegiline orally disintegrating tablets, discontinuance of therapy because of adverse effects was required in 5% of selegiline-treated patients and 1% of placebo recipients; such adverse effects included dizziness, chest pain, accidental injury, and myasthenia.144 The most common adverse effects observed in these studies and that occurred at an incidence at least 3% higher than that observed with placebo included constipation, skin disorders, vomiting, dizziness, dyskinesia, insomnia, dyspnea, myalgia, and rash.144

Nervous System and Muscular Effects

In patients receiving levodopa, addition of selegiline may exacerbate levodopa-associated dyskinesias.1,2,5,49,50,64,66,68,144 This effect, which has been reported to occur in an average of 28% (range: 4-90%) of patients receiving the drug in clinical trials, usually occurs within 2 weeks after initiating selegiline therapy5,6 and generally is mitigated when the levodopa dosage is reduced.1,5,6 Involuntary movements,1,2 increased tremor,1,2 chorea,1,2 loss of balance,1,2 freezing,1,2 blepharospasm,1,2 increased bradykinesia,1,2 facial grimacing,1,2 falling,1,2 speech problems,1,2 heavy leg,1,2 stiff neck,1,2 tardive dyskinesia,1,2 dystonic manifestations,1,2 festination,1,2 increased apraxia,1,2 and muscle cramping1,2 may occur in patients receiving selegiline.1,2 Bruxism,1,2 muscle twitching1,2 and myoclonic jerks1,2 have occurred in patients receiving levodopa and selegiline hydrochloride dosages exceeding 10 mg daily (as conventional oral preparations).1,2

Numerous CNS and psychiatric disturbances have occurred in patients receiving selegiline, including hallucinations,1,2,5,49,50,64,66,67 confusion,1,2,5,40,50,64,66,67,68 dizziness,1,2,5,6,50,68 lightheadedness,1,2 fainting,1,2,68 vertigo,1,2 vivid dreams,1,2,5,50 sleep disturbances/insomnia,1,2,5,12,75 headache1,2,5,50 (including migraine),1,2 anxiety,1,2,12,50 depression,1,2 delusions,1,2,50 disorientation,1,2 hollow feeling,1,2 apathy,1,2 psychosis/behavior/mood changes,1,2,5,50,66,75 personality change,1,2 drowsiness/tiredness,1,2 fatigue/lethargy/malaise,1,2,50 overstimulation,1,2,75 restlessness,1,2,68,75 weakness,1,2 and transient irritability.1,2 Most of these effects presumably result from increased dopaminergic activity rather than from the amphetamine metabolites of selegiline.5 Other events occurring in parkinsonian patients receiving levodopa and selegiline hydrochloride dosages exceeding 10 mg daily (as conventional oral preparations) include increased energy,1,2 transient high,1,2 and impaired memory.1,2 Seizure occurred in one patient with chronic renal failure requiring dialysis who was receiving selegiline and other drugs.1,2

GI Effects

Nausea1,2,5,6,39,50,66 has been reported in 10%,1,2 abdominal pain1,2,39,50 in 4%,1,2 and dry mouth1,2,50 in 3%1,2 of patients receiving selegiline in a placebo-controlled clinical trial.1,2 Vomiting,1,2,5,39 anorexia (which may be accompanied by weight loss),1,2,12 poor appetite,1,2 constipation,1,2 and diarrhea1,2,50 also have been reported in patients receiving selegiline. Other adverse effects reported in patients receiving selegiline and levodopa include GI bleeding,1,2,5,66 peptic ulcer,1,2,5,6 heartburn,1,2,5 rectal bleeding,1,2,66 dysphagia,1,2,50 and change in taste sensation.1,2

Cardiovascular Effects

Cardiac arrhythmias1,2 (including tachycardia1,2 and sinus bradycardia),1,2 palpitations,1,2 hypertension,1,2,5,76 hypotension,1,2 orthostatic hypotension,1,2,5,68,76 syncope,1,2,5,68 peripheral edema,1,2 angina pectoris,1,2 and exacerbation of angina pectoris1,2 have occurred in patients receiving selegiline.1,2

Rarely, hypertensive reactions, including at least one case of hypertensive crisis, have occurred at usual dosages (10 mg daily as conventional oral preparations) of selegiline hydrochloride in association with ingestion of tyramine-containing foods or a sympathomimetic drug.1 (See Drug Interactions.)

In controlled clinical studies of selegiline orally disintegrating tablets, orthostatic hypotension consisting of decreases in systolic and diastolic blood pressure of at least 20/10 mm Hg occurred more frequently with selegiline than with placebo.144 Orthostatic hypotension was reported most frequently at 8 weeks, corresponding to the period following an increase in dosage.144

Genitourinary Effects

Prostatic hypertrophy,1,2 slow urination,1,2 urinary hesitancy,1,2 urinary retention,1,2,50,68 nocturia,1,2 urinary frequency,1,2 and sexual dysfunction1,2 have occurred in patients receiving selegiline. Adverse events reported in patients receiving selegiline hydrochloride dosages exceeding 10 mg daily (as conventional oral preparations) include transient anorgasmia1,2 and decreased penile sensation.1,2

Small increases in serum creatinine and BUN have occurred in some patients receiving high dosages of selegiline hydrochloride orally disintegrating tablets (10 mg daily).144

Dermatologic Effects

Data from epidemiologic studies indicate that patients with Parkinson disease have a twofold to approximately sixfold greater risk of developing melanoma than the general population.1,2 It is unclear whether the observed increased risk is due to Parkinson disease or other factors (e.g., drugs used to treat the disease).1,2 (See Cautions: Precautions and Contraindications.)

Intense Urges

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

Other Adverse Effects

Generalized ache,1,2 back pain,1,2,50 leg pain,1,2 and supraorbital pain1,2 have occurred in patients receiving selegiline. Other adverse effects reported in patients receiving the drug include tinnitus,1,2 chills,1,2 burning throat,1,2 blurred vision,1,2 diplopia,1,2 numbness in toes/fingers,1,2 increased sweating,1,5 diaphoresis,1,2 shortness of breath,1,2 facial hair,1,2 hair loss,1,2 and hematoma.1,2 Asthma,1,2 rash,1,2 and photosensitivity reactions have occurred.1,2 Transient elevations in liver enzyme values have occurred in patients receiving selegiline.5,6,64 Hypoglycemia with hyperinsulinemia occurred in one patient following addition of selegiline to an antiparkinsonian treatment regimen that included levodopa/carbidopa, amantadine, and bromocriptine.69 In controlled clinical studies of selegiline orally disintegrating tablets, an increased frequency of mild oropharyngeal abnormality (e.g., swallowing pain, mouth pain, areas of focal reddening, edema, multiple foci of reddening, and/or ulceration) was reported in patients receiving the drug.144

Precautions and Contraindications

Because of the risk of adverse effects associated with nonselective inhibition of monoamine oxidase (i.e., inhibition of both monoamine oxidase [MOA]-A and MOA-B), patients should not exceed recommended dosages of selegiline hydrochloride (10 mg daily when using conventional oral preparations and 2.5 mg daily when using orally disintegrating tablets).1,2,144 (See Pharmacology.) In addition, patients should be advised of the risk of serious adverse effects, including hypertensive reaction (i.e., cheese reaction), if recommended dosages are exceeded.1,2,144 Because such reactions rarely have occurred even at recommended dosages of the drug when tyramine-containing foods or a sympathomimetic drug was used concomitantly, patients should be warned of this possibility (see Drug Interactions) and advised to contact a clinician if signs or symptoms of hypertension, such as headache, neck stiffness or soreness, or palpitation, or other unusual symptoms occur.1,2,122

Selegiline may exacerbate levodopa-associated adverse effects in some patients, presumably by increasing dopaminergic activity; most of these adverse effects can be mitigated by reducing the dosage of levodopa.1,2,5,68 (See Cautions: Nervous System and Muscular Effects.) Patients should be advised of the possible need to reduce levodopa dosage after initiation of selegiline therapy.1,2 (See Dosage and Administration: Dosage.)

Severe, sometimes fatal, serotonin syndrome has been reported in patients receiving MAO inhibitors concomitantly with antidepressants.1,2,144 Manifestations may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular aberrations (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,126,131,133 (See Drug Interactions: Antidepressant Agents.)

Changes in mental status or behavior may occur during selegiline therapy.144 Patients with major psychotic disorders generally should not receive selegiline due to the risk of exacerbating psychosis with an increase in central dopaminergic tone.144 Additionally, the symptoms of Parkinson disease may be exacerbated by antipsychotic agents that antagonize the effects of dopaminergic drugs.144 (See Drug Interactions: Other Drugs.)

Patients receiving dopaminergic drugs have reported falling asleep while engaged in activities of daily living including operating a motor vehicle (which has sometimes resulted in accidents).144 Patients may not exhibit warning signs (e.g., excessive drowsiness) or may report feeling alert immediately prior to the sudden sleep event.144 If a patient develops clinically important daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), selegiline generally should be discontinued.144 If a decision is made to continue the drug, patients should be advised not to drive and to avoid other potentially dangerous activities.144

Symptoms resembling neuroleptic malignant syndrome (e.g., muscular rigidity, altered consciousness, autonomic instability) have been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.144 Patients should be advised to contact their clinician if they wish to discontinue therapy or decrease dosage of selegiline.144

Because the risk of developing melanoma is increased in patients with Parkinson disease compared with the general population, patients should be monitored for melanoma on a frequent and regular basis.1,2 The manufacturers recommend that dermatologic examinations be performed periodically by qualified clinicians (e.g., dermatologists).1,2

Intense urges have been reported with selegiline; therefore, clinicians should ask patients whether they have developed new or increased gambling urges, sexual urges, or other urges while receiving selegiline and should advise them of the importance of reporting such urges.1,2,144 If a patient develops such urges while receiving selegiline, consideration should be given to reducing the dosage or discontinuing the drug.1,2,144

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that each 1.25-mg selegiline orally disintegrating tablet (Zelapar^®) contains aspartame (NutraSweet^®) which is metabolized in the GI tract to provide about 1.25 mg of phenylalanine following oral administration.144,145,146,147,148,149

Selegiline hydrochloride is contraindicated in patients with known hypersensitivity to the drug.1,2,144 The drug also is contraindicated in patients receiving other MAO inhibitors (selective or nonselective), certain opiate agonists (e.g., meperidine, methadone, propoxyphene [no longer commercially available in the US], tramadol), cyclobenzaprine, St. John's wort ( Hypericum perforatum ), and dextromethorphan.1,2,144 (See Drug Interactions.)

Pediatric Precautions

Safety and efficacy of selegiline have not been established in pediatric patients.1,2,144

Geriatric Precautions

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

Certain adverse effects (e.g., hypertension, orthostatic hypotension) have been reported with greater frequency in geriatric patients 65 years of age or older compared with younger individuals.144

Following administration of a single 10-mg dose of selegiline hydrochloride (as a conventional oral formulation) in a limited number of adults 60 years of age or older, systemic exposure was twice the value reported in adults 18-30 years of age.1,2

Mutagenicity and Carcinogenicity

No evidence of mutagenicity or chromosomal damage was observed in the bacterial mutation assay in Salmonella typhimurium or in an in vivo chromosomal aberration assay.1,2,71 While these results suggest selegiline is not mutagenic or clastogenic, these studies were not definitive because of methodologic limitations, and additional study (i.e., definitive in vitro chromosomal aberration or in vitro mammalian gene mutation assays) is needed to establish the mutagenic and carcinogenic potential of selegiline.1,2,71

Carcinogenicity studies have not been conducted to date using selegiline orally disintegrating tablets.144

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats given oral selegiline hydrochloride dosages of 4, 12, or 36 mg/mg (4, 12, or 35 times the human therapeutic dose on a mg/m² basis) have not revealed teratogenic effects.1,2 However, there was a decrease in fetal body weight at the highest dose evaluated.1,2 In a perinatal and postnatal development study in rats given oral dosages of 4, 16, or 64 mg/kg (4, 15, or 62 times the human therapeutic dose on a mg/m² basis), an increase in the number of stillbirths and a decrease in the number of pups per dam, pup survival, and pup weight (at birth and throughout the lactation period) occurred at the two highest dosage levels.1,2 Because none of the pups born alive survived to day 4 postpartum at the highest dose, postnatal development of these pups could not be evaluated.1,2

Reproduction studies in rabbits given oral selegiline hydrochloride dosages of 5, 25, or 50 mg/kg (10, 48, or 95 times the human therapeutic dose on a mg/m² basis) have not revealed teratogenic effects; however, the number of litters produced at the 2 highest dosage levels was lower than that recommended for assessment of teratogenic potential.1,2 An increase in total resorptions and percent postimplantation loss, and a decrease in the number of live fetuses per dam was observed at the highest dose level.1,2

There are no adequate and controlled studies to date using selegiline in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1,2,144

Fertility

The effect of selegiline on fertility has not been evaluated.1,2

Lactation

It is not known whether selegiline is distributed into human milk; the drug is distributed into milk in rats.1,2,144 Because many drugs are distributed into human milk, selegiline should be used with caution in nursing women.144 Some manufacturers state that consideration should be given to discontinuing the use of all but absolutely essential drug therapy in nursing women.1,2

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro studies indicate that selegiline is metabolized by cytochrome P-450 (CYP) 2B6, CYP3A4, and possibly CYP2A6 (to a lesser extent).144 In vitro studies also demonstrate that selegiline is not an inhibitor of CYP enzymes and has little or no potential for inducing CYP1A2 and CYP3A4/5 under usual clinical conditions.144

Concomitant administration of itraconazole (a CYP3A inhibitor) with selegiline did not alter the pharmacokinetics of selegiline.144 Specific drug interaction studies have not been conducted to evaluate the effects of CYP3A4 inducers (e.g., phenytoin, carbamazepine, nafcillin, phenobarbital, rifampin) on the pharmacokinetics of selegiline; if CYP3A4 inducers are used concomitantly with selegiline, caution is advised.144

Antidepressant Agents

Serotonergic Agents

Concomitant use of selective (e.g., selegiline, rasagiline) or nonselective (e.g., phenelzine, tranylcypromine) monoamine oxidase (MAO) inhibitors with antidepressants (e.g., selective serotonin-reuptake inhibitors [SSRIs], selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], tricyclic or tetracyclic antidepressants, triazolopyridine-derivative antidepressants) has resulted in severe, sometimes fatal, serotonin syndrome.1,2,13,16,17,97,99,100,101,112,131,144 (See Drug Interactions: Serotonergic Drugs in Fluoxetine 28:16.04.20.) Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,126,131,133

In general, concomitant use of selegiline with any antidepressant should be avoided.1,2,17,99,100,101,144 At least 2 weeks should elapse between discontinuance of selegiline and initiation of therapy with an SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant.1,2,17,99,100,101,144 Because both fluoxetine and its principal metabolite have relatively long half-lives, the manufacturers recommend that at least 5 weeks elapse between discontinuance of fluoxetine and initiation of selegiline therapy; a longer interval should be considered in patients who received long-term or high-dosage fluoxetine therapy.1,2,17,144 Administration of an MAO inhibitor within 5 weeks following discontinuance of fluoxetine may increase the risk of serious adverse effects.17 At least 2 weeks should elapse between discontinuance of other SSRIs (i.e., fluvoxamine, paroxetine, sertraline) and initiation of selegiline.99,100,101 At least 2 weeks also should elapse between discontinuance of tricyclic antidepressant therapy and initiation of selegiline therapy.102,103

Tyramine-rich Foods

Hypertensive crises following ingestion of foods containing large amounts of tyramine (i.e., cheese reaction) have occurred in patients receiving nonselective monoamine oxidase (MAO) inhibitors.123 While it previously was thought that similar hypertensive reactions were unlikely in patients receiving recommended dosages of selegiline hydrochloride,4,5,112,122 and some clinicians and manufacturers actually previously stated that dietary restrictions were unnecessary at such dosages,4,5,112 it now is known that hypertensive reactions can occur rarely at the recommended antiparkinsonian dosa therefore, caution should be exercised whenever selegiline is used regardless of dosage.1

Nonselective inhibition of MAO increases the risk of hypertensive reactions; selectivity for MAO-B typically decreases as dosage of selegiline hydrochloride is increased above recommended dosages (10 mg daily with conventional oral preparations or 2.5 mg daily with orally disintegrating tablets).1,2,144 Although the precise dosage at which selegiline hydrochloride becomes a nonselective inhibitor of MAO is not known, it may be 30-40 mg daily (when given as conventional oral preparations) or 5 mg daily (when given as orally disintegrating tablets).1,2,5,9,10,11,12,113,144 Patients should be advised not to exceed the recommended dosages of selegiline hydrochloride.1,2,144 Patients receiving selegiline should be instructed to avoid foods and beverages with a high tyramine content.144 Rare cases of hypertensive reactions have been reported when selegiline hydrochloride conventional oral preparations were given at the usual dosage of 10 mg daily as a result of dietary indiscretion with tyramine-containing foods.1 The manufacturer of selegiline hydrochloride orally disintegrating tablets states that safe use of the drug at dosages above 2.5 mg daily without dietary tyramine restrictions has not been established.144 Specialized references on food constituents or a dietician should be consulted for specific information on the tyramine content of foods and beverages.122

Monoamine Oxidase Inhibitors

Concomitant use of selegiline with other MAO inhibitors (selective or nonselective) may increase the risk of nonselective MAO inhibition, possibly resulting in hypertensive crisis; concomitant use is contraindicated.144 At least 14 days should elapse between discontinuance of selegiline and initiation of therapy with other MAO inhibitors.144

Opiate Agonists

Serotonin syndrome has been reported in some patients receiving selegiline concomitantly with meperidine; manifestations resolved over several days following discontinuance of both drugs.1,144 Other serious adverse effects reported following concomitant use of an MAO inhibitor with meperidine include severe agitation, hallucinations, and death.1,2,21,112,118

The manufacturers of selegiline state that concomitant use of selegiline with meperidine, methadone, propoxyphene (no longer commercially available in the US), or tramadol is contraindicated .1,2,144 At least 14 days should elapse between discontinuance of selegiline and initiation of therapy with these opiate agonists.144 Consideration should be given to discontinuing selegiline 2 weeks prior to scheduled surgery if postoperative meperidine analgesia is possible.112 While morphine theoretically would be less likely than meperidine to interact with selegiline, the safety of opiate use in general remains to be established for patients receiving selegiline.118,122

Sympathomimetic Drugs

Severe hypertension or hypertensive crisis may occur following concomitant use of selegiline with sympathomimetic drugs.1 Hypertensive crisis was reported in at least one patient receiving the recommended 10-mg daily dosage of selegiline hydrochloride (as a conventional oral preparation) and a sympathomimetic agent (ephedrine).1,2

Other Drugs

Dopamine antagonists such as metoclopramide and certain antipsychotic agents may potentially diminish the efficacy of selegiline.144

Psychosis and bizarre behavior have been reported in patients receiving dextromethorphan and MAO inhibitors concomitantly; concomitant use of dextromethorphan and selegiline is contraindicated.144

Concomitant use of selegiline with St. John's wort (Hypericum perforatum) or cyclobenzaprine is contraindicated.144

Acute Toxicity

Limited information is available on the acute toxicity of selegiline hydrochloride.1,2

Pathogenesis

Acute toxicity studies in animals revealed that the LD₅₀s for selegiline hydrochloride administered orally, IV, subcutaneously, or intraperitoneally are approximately 200-445, 40-75, 95-206, or 190 mg/kg, respectively.4,70

Manifestations

The manufacturers state that there has been no experience to date with intentional, acute overdosage of selegiline hydrochloride.1,2 Selegiline hydrochloride conventional tablets and capsules at dosages exceeding 10 mg daily (e.g., 30-40 mg daily) and selegiline hydrochloride orally disintegrating tablets at dosages exceeding 2.5 mg daily are likely to inhibit both MAO-A and MAO-B.1,2,7,144 Therefore, overdosage of selegiline hydrochloride would be expected to produce signs and symptoms consistent with those observed with overdosage of nonselective MAO inhibitors.1,2,144 (See Acute Toxicity: Manifestations, in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.) Animal studies indicate that possible effects of selegiline overdosage include ataxia, piloerection, dyspnea, hyperpnea, restlessness, salivation, listlessness, aggression, abnormal behavior, and seizures.70 In preclinical studies, severe hypotension and psychomotor agitation occurred in individuals given 600 mg of racemic dimethyl propynylphenethylamine ( d,l -selegiline).1,2

Treatment

There is no experience to date in the management of acute overdosage of selegiline hydrochloride.1,2 The manufacturers recommend that, in the event of selegiline hydrochloride overdosage, treatment be instituted following treatment guidelines for nonselective MAO inhibitor overdose.1,2 The manufacturer of selegiline orally disintegrating tablets states that there is no experience in cases of overdosage resulting from swallowing of the tablet.144 (See Acute Toxicity: Treatment, in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.) In addition, a regional poison control center may be consulted for additional information.1,2

Pharmacology

Selegiline is a relatively selective inhibitor of monoamine oxidase-B (MAO-B); however, selectivity is not absolute, and inhibition of MAO-A occurs at relatively high doses.1,2,4,5,22 The principal physiologic action of selegiline at the dosage used in the management of parkinsonian syndrome is to irreversibly inhibit monoamine oxidase-B (MAO-B) within the nigrostriatal pathways in the CNS.1,2,4,5,22

Monoamine oxidase (MAO), a mitochondrial enzyme, catalyzes the oxidative deamination of various amines, including neuronal transmitters.1,2,4,5,22,41,84 MAOs are widely distributed throughout the body, with the highest concentrations occurring in liver, kidney, stomach, intestinal wall, and brain.1,2 There appear to be at least 2 isoforms of monoamine oxidase, MAO-A and MAO-B, with differences in substrate preference, inhibitor specificity, tissue distribution, immunologic properties, and amino acid sequence.1,2,4,5,22,41,84 In humans, MAOs in the brain are predominately type B and those in the intestine are predominately type A.1,84 MAO-A substrates include serotonin; MAO-B substrates include phenylethylamine.41,84 Tyramine, epinephrine, norepinephrine, and dopamine are substrates for both MAO-A and MAO-B.41,84 Inhibition of MAO results in increased concentrations of these amines.1,2,4,5,22,41

Selegiline has been referred to as a suicide inhibitor of MAO since the drug irreversibly inactivates the enzyme.1,2,4,5,22,25,41,84 Initially, selegiline binds reversibly with MAO; the resulting diazene intermediary is highly reactive and binds irreversibly through covalent attachment to the N-5 position of the essential flavin adenine dinucleotide (FAD) cofactor and/or the active site.1,2,4,5,22,41,42 Because selegiline is an irreversible MAO inhibitor, resumption of MAO activity depends on regeneration of the enzyme.33,34 Limited evidence indicates that the turnover rate for MAO-B in the CNS is about 40 days in humans.86 In one animal species (baboons), the half-life of enzyme turnover in brain tissue was 30 days.33,86 While platelet MAO-B activity returns to normal values within 5-7 days after discontinuing selegiline, the relationship between platelet and CNS MAO-B inhibition has not been determined.1 Because selegiline has greater affinity for MAO-B than MAO-A, it is a selective MAO inhibitor.1,2,4,5,22,25,32,41

When given at recommended dosages (10 mg daily using conventional oral preparations or 2.5 mg daily using orally disintegrating tablets), selegiline hydrochloride selectively inhibits cerebral MAO-B while having little effect on MAO-A in the GI tract and liver.1,2,4,5,22,32,84,144 MAO-A in intestinal tissue is approximately 1000 times less sensitive to inhibition by selegiline than platelet MAO-B.44 At higher dosages (e.g., 30-40 mg daily with conventional oral preparations or 5 mg daily with orally disintegrating tablets), this selectivity of selegiline for MAO-B usually diminishes, and the drug will inhibit MAO-B and MAO-A.1,2,4,5,22,32,144

An important characteristic of parkinsonian syndrome is the loss of dopaminergic neuron cell bodies in the zona compacta of the substantia nigra, resulting in striatal dopamine denervation.84 While the precise mechanism of neuronal death in patients with parkinsonian syndrome remains to be determined,84 several etiologic hypotheses have been suggested, including exogenous toxins, mitochondrial abnormalities, free radical formation, and auto-oxidation.83,84,85 However, the manifestations of parkinsonian syndrome, regardless of cause of the syndrome, are related to depletion of dopamine in the corpus striatum.83,84,85

While the complete mechanisms of activity of selegiline in the management of parkinsonian syndrome have not been fully elucidated, the drug is believed to act principally by blocking microsomal metabolism of dopamine in the brain.1,2,4,5,22 By inhibiting MAO-B-mediated metabolism, dopaminergic activity in the substantia nigra is enhanced.1,2,4,5,22 Selegiline may increase dopaminergic activity by mechanisms other than inhibition of MAO-B; there is some evidence that selegiline interferes with dopamine reuptake at the synapse.1,2,5,84 Selegiline reduces the amount of levodopa required to maintain optimum dopamine concentrations in the brain of patients with parkinsonian syndrome.1,2,4,5,22 Autopsy findings in patients with parkinsonian syndrome who were receiving long-term levodopa therapy and had received selegiline hydrochloride 10 mg daily (as conventional oral preparations) for about 6 days prior to death demonstrated substantial inhibition of brain MAO activity; dopamine deamination was reduced by 94 and 92% (range: 86-95%) in substantia nigra homogenates and other brain tissues, respectively, compared with controls (individuals without parkinsonian syndrome).5,24 In addition, dopamine concentrations were about 70% higher in substantia nigra tissue in patients with parkinsonian syndrome receiving selegiline compared with such patients not receiving the drug.5,22

Selegiline also may prevent or delay neuronal death by protecting the nigral neurons from damage by oxygen free radicals produced through MAO-B activity.4,5,83,84,85,104,105 The gradual decline in the number of dopaminergic nigral neurons, such as occurs in parkinsonian syndrome, in patients with Alzheimer's disease, and possibly in normal aging, may result in a compensatory increase in dopamine turnover and free radical production.4,5,43,83,84,85,104 By inhibiting MAO-B, selegiline may limit formation of hydrogen peroxide resulting from increased nigrostriatal dopamine turnover, and thus protect remaining dopaminergic neurons from oxygen radical-induced degeneration.4,5,83,84,104

Selegiline prevents MAO-B mediated production of the neurotoxin methyl-4-phenylpyridinium ion (MPP⁺) from phenyl-1,2,3,6-tetrahydropyridine (MPTP).4,5,83,84 MPP⁺ selectively destroys neurons in the substantia nigra and causes manifestations similar to those of idiopathic parkinsonian syndrome in animals and humans.4,5 Animal studies indicate that selegiline, by inhibiting oxidation of MPTP to MPP⁺, prevents signs and symptoms of MPTP-induced neuronal damage.4,5,58 If an MPTP-like substance contributes to the pathogenesis of parkinsonian syndrome, the inhibition of oxidation of such a substance may protect against its neurotoxic effects.4,5,83,84

The ability to promote neuronal survival and neurite outgrowth and the release of dopamine from intact neurons, and to block the activation of the N -methyl-d-aspartate (NMDA) sensitive population of receptors for glutamate may contribute to selegiline's activity.4,5,22,23,43,78,79,80,81,82,83,84,85

The extent to which the major metabolites of selegiline, l -methamphetamine and l -amphetamine, contribute to the effect of the drug in parkinsonian syndrome has not been determined.1,2,5,32

For information on antidepressant activity of MAO inhibitors, see Pharmacology in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.

Pharmacokinetics

Limited information is available on the pharmacokinetics of selegiline in humans, but pharmacokinetics of the drug exhibit considerable interindividual variation.1,2,5,26,27,28,29,30,31,32,44,87,88,108 Following oral administration of usual therapeutic doses of selegiline hydrochloride, concentrations of the parent drug in serum or urine were below the level of detection (10 ng/mL) of most early analytical methods.5,44,108 However, an enzymatic method with a lower limit of detection of 0.25 ng/mL,87,108 a gas chromatographic-mass spectrophotometric method with a lower limit of detection of 0.05 ng/mL,108,110 and another method with a lower limit of detection of 0.01 ng/mL have been developed, and limited pharmacokinetic data from studies employing these assay methods have been reported.87,108,110 Pharmacokinetic data also has been derived from studies using radiolabeled selegiline and from studies measuring concentrations of the main metabolites, l -desmethyl selegiline, l -methamphetamine, or l -amphetamine.1,2,5,26,27,28,29,30,31,32,33,44,72

Absorption

Selegiline hydrochloride conventional tablets and capsules are rapidly absorbed following oral administration, with peak plasma selegiline concentrations of 0.9-2.7 ng/mL occurring within 0.5-0.9 hours in fasting individuals.86,87,108,110 The drug is extensively metabolized during first pass through the gut wall and liver to l -desmethylselegiline, l -methylamphetamine, and l -amphetamine.1,32,108 An oral bioavailability of 10% has been reported for selegiline hydrochloride conventional tablets.108 The relative oral bioavailability of selegiline hydrochloride conventional tablets versus oral solution is 76%.108 Presence of food in the GI tract increases oral bioavailability of selegiline (as conventional oral preparations) threefold to fivefold, but does not appear to affect the pharmacokinetics of the first-pass metabolites.1,108

Following oral administration of a single 10-mg dose of selegiline hydrochloride (as a conventional oral preparation), peak plasma concentrations of l -desmethylselegiline, l -methamphetamine, and l -amphetamine are 3- to 20-fold higher than the peak plasma concentrations of selegiline.1,108,110 In healthy adults, mean peak l -desmethylselegiline, l -methamphetamine, and l -amphetamine concentrations of 7.8-20, 10.2-40, and 3.6-30 ng/mL, respectively, were achieved following oral administration of a single 10-mg dose of selegiline hydrochloride and concentrations of 24, 40, and 20 ng/mL, respectively, following oral administration of selegiline hydrochloride 10 mg daily for 7 days.5,12,29,44,108,110 Following oral administration of selegiline hydrochloride 10 mg daily for 7 days as a conventional oral formulation in healthy adults, trough serum l -methamphetamine and l -amphetamine concentrations averaged 8 and 3.5 ng/mL, respectively; trough concentrations of l -desmethylselegiline were below the level of detection.5 Trough serum concentrations of l -desmethylselegiline, l -methamphetamine, and l -amphetamine averaged 1.3, 9, and 5.8 ng/mL, respectively, following long-term administration of selegiline hydrochloride 10 mg daily in a limited number of adults with parkinsonian syndrome.32,44 Results from single-dose studies differ from multiple-dose studies.1,108 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 administration of a single dose.1,108

Absorption of selegiline from the orally disintegrating tablet formulation is more rapid than from conventional oral formulations and occurs predominately through the buccal mucosa.144,158 Mean peak plasma concentrations of 3.34 or 4.47 ng/mL are achieved within 10-15 minutes following buccal administration of single doses of selegiline hydrochloride 1.25 or 2.5 mg, respectively, as orally disintegrating tablets.144,155 Dose-proportional increases in peak plasma concentrations and area under the concentration-time curve (AUC) of selegiline are observed following administration of doses ranging from 1.25-10 mg, and steady state is achieved after 8 days with the orally disintegrating tablets.144,156 Following administration of the orally disintegrating tablet, the drug undergoes pregastric absorption and substantially bypasses first-pass metabolism, resulting in increased plasma concentrations of selegiline and decreased concentrations of amphetamine metabolites compared with those achieved with conventional oral preparations.144,150,155,156,158 Administration of the orally disintegrating tablets with food decreases AUC and peak plasma concentrations of the drug to approximately 60% of those seen when administered in the fasted state.144 (See Dosage and Administration: Administration.)

In healthy adults, platelet MAO-B activity was inhibited by 90% following oral administration of selegiline hydrochloride 10 mg (as conventional oral preparations) and by 99.9% following administration of 10 mg daily for 1 week.44,45

Selegiline also is well-absorbed percutaneously following topical application to the skin as a transdermal system (not commercially available in the US).108,109,111 However, unlike absorption from the GI tract, the drug does not undergo first-pass metabolism (i.e., in the skin) during percutaneous absorption, thus achieving plasma concentrations of unchanged drug that are proportionately higher than those achieved with oral administration.108,109,111

Distribution

Selegiline and its metabolites are widely distributed into body tissues and cross the blood-brain barrier.1,2,5,27,28,29,30,31,32,44 Following IV administration of radiolabeled selegiline hydrochloride in mice, the parent drug and/or metabolites are rapidly and widely distributed to brain, liver, kidney, lung, heart, and brown fat.5,29 Following IV administration of radiolabeled selegiline hydrochloride in healthy adults, the highest accumulation of radioactivity occurred in the thalamus, basal ganglia, mesencephalon, and cingulate gyrus.27,28

Metabolites of selegiline have been detected in brain tissue; l -amphetamine concentrations of up to 56 ng/g in brain tissue (i.e., thalamus) have been reported at autopsy in patients with parkinsonian syndrome who had received selegiline hydrochloride 5-10 mg daily (as conventional oral preparations) for 3-18 days prior to death.2,5,30,44 CSF concentrations of l -desmethylselegiline, l -methamphetamine, and l -amphetamine were 0.7, 14.2, and 6.3 ng/mL, respectively, following long-term administration of selegiline hydrochloride 10 mg daily (as conventional oral preparations) in a limited number of patients with parkinsonian syndrome.32,44 CSF concentrations of l -desmethylselegiline, l -methamphetamine, and l -amphetamine averaged 1.1, 15, and 7 ng/mL, respectively, in a limited number of patients with dementia of the Alzheimer's type receiving selegiline.32,44 Selegiline metabolites also have been detected in the liver.29 Following oral administration of selegiline hydrochloride 15 mg daily for 5 days in a limited number of healthy adults, concentrations of selegiline, l -desmethylselegiline, l -methylamphetamine, or l -amphetamine detected in hair on day 21 were trace level, 0.17-0.29, 1.3-2.25, or 0.42-0.99 ng/mg, respectively.88

Selegiline and/or its metabolites are up to 94% bound to plasma proteins.5,31,32,44 The volumes of distribution of the parent drug and/or metabolites have been reported to be about 300 L,5,31,32 but an apparent volume of distribution of 1850 L has been reported for unchanged drug in at least one study.108

Elimination

Selegiline is extensively metabolized, presumably through cytochrome P-450 (CYP)-mediated metabolism involving CYP2B6, CYP3A4, and possibly CYP2A6 (to a lesser extent), to form l -desmethylselegiline and l -methamphetamine, which is further metabolized to l -amphetamine.5,12,26,27,28,29,30,31,32,44,108,110,144 Selegiline also is metabolized in the lungs to l -desmethylselegiline and l -methamphetamine and in the kidneys to l -methamphetamine, but the degree of metabolism in these tissues is minimal compared with that in the liver.5,32,108

l -Desmethylselegiline is an irreversible inhibitor of monoamine oxidase-B (MAO-B).1,32,44,45,46,47,110 Although the inhibitory potency of this metabolite has been reported to be similar to that of the parent drug,32,44,45,46,47 other evidence indicates that the MAO-B inhibitory potential of selegiline is 5 times that of l -desmethylselegiline, and that the contribution of this metabolite to MAO-B inhibition during selegiline therapy may be only minor.110 At concentrations achieved clinically, l -methamphetamine and l -amphetamine do not inhibit MAO-B.1,32 l -Methamphetamine and l -amphetamine are CNS stimulants; however, the amphetamine metabolites of selegiline are levorotatory isomers and are less potent CNS stimulants than the racemic or dextrorotatory isomers.5,26,44 l -Methamphetamine and l -amphetamine also may be metabolized to p -hydroxymethamphetamine and p -hydroxyamphetamine, respectively; these para-hydroxylated metabolites are then conjugated with glucuronic acid.5,32,88,108

An elimination half-life of approximately 1.2-2 hours for selegiline has been reported following administration of a single oral 10-mg dose (as conventional tablets) or a single dose of 2.5 mg (as orally disintegrating tablets),1,87,108,144 and a half-life of about 10 hours has been reported at steady state.1,108,144 Elimination half-lives of 2, 20.5, and 17.7 hours have been reported for l -desmethylselegiline, l -methamphetamine, and l -amphetamine, respectively.2,44

Selegiline is excreted principally in urine as conjugated and unconjugated metabolites.5,12,26,27,28,29,30,31,32,44 About 20-63% of an orally administered dose of selegiline is excreted in urine as l -methamphetamine, 9-26% as l -amphetamine, and 1% as l -desmethylselegiline.5,12,31,44 Urinary excretion of amphetamines is pH dependent and excretion is enhanced in acidic urine.5,31,44 Varying the urinary pH between 6.5-7.4 produced substantial changes in the urinary excretion rate of l -methamphetamine and l -amphetamine in a limited number of patients with parkinsonian syndrome; however, clinical response to selegiline was not affected.5,31,44 About 15% of a dose is excreted in feces within 72 hours following administration of selegiline.44

Chemistry and Stability

Chemistry

Selegiline hydrochloride, a relatively stereoselective monoamine oxidase-B (MAO-B) inhibitor, is the levorotatory isomer of dimethyl propynylphenethylamine1,2,3 and is structurally related to pargyline (not commercially available in the US).3 Selegiline, like pargyline, contains an propargyl group on the nitrogen which results in irreversible MAO inhibition.4,25 Compounds, such as selegiline, with a distance equivalent to 1 or 2 carbon units between the aromatic ring and N -propargyl exhibit relative selectivity for MAO type B.4,25 Selegiline is pharmacologically distinct from nonselective MAO inhibitors such as isocarboxazid (no longer commercially available in the US), phenelzine sulfate, tranylcypromine sulfate, and pargyline hydrochloride.1,2,4 In general, the dextro enantiomer of dimethyl propynylphenethylamine does not inhibit MAO.32,42

Selegiline hydrochloride occurs as a white to off-white crystalline powder.1,2 Selegiline hydrochloride is freely soluble in water, chloroform, and methanol.1,2 The drug has a pK_a of 7.5.109

Stability

Commercially available selegiline hydrochloride capsules and tablets should be stored at 20-25°C.1,2

Selegiline hydrochloride orally disintegrating tablets should be stored at 25°C but may be exposed to 15-30°C.144 Tablets should be used within 3 months of opening the pouch and immediately upon opening the individual blister.144

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