Selegiline Hydrochloride

AHFS Class: Monoamine Oxidase B Inhibitors (28:36.32)

VA Class: CN500
VA Class: CN602
Chemical Name: (R)-N,α-Dimethyl-N-2-propynyl-benzeneethanamine hydrochloride
Molecular Formula: C₁₃H₁₇N•ClH

L-Deprenyl

View the associated Essentials monograph.

Introduction

Selegiline hydrochloride, a relatively stereoselective monoamine oxidase-B (MAO-B) inhibitor, is the levorotatory isomer of dimethyl propynylphenethylamine that is used in parkinsonian syndrome.^{1 2 3}

Uses

Parkinsonian Syndrome

Selegiline hydrochloride is used for the symptomatic treatment of parkinsonian syndrome.^{1 2 4 5 6 7 8 34 35 36 37 38 39 40 53 54 55 56 65 66 73 85 89 90 91 92 93} Selegiline hydrochloride is used as adjunctive therapy in parkinsonian patients who exhibit a deteriorating response to levodopa/carbidopa therapy and is designated as an orphan drug by the US Food and Drug Administration (FDA) for this condition.^{1 2 4 5 6 7 8 34 35 36 37 38 39 40 65 66 85 92 93} Selegiline also has been used effectively as monotherapy in patients with newly diagnosed parkinsonian syndrome†.^{5 7 53 54 55 56 73 84 85 93}

Levodopa (with or without carbidopa) currently is the most effective drug for relieving the manifestations of parkinsonian syndrome.^{8 11 65 66 85 89} However, the effectiveness of levodopa decreases substantially after the third year of treatment, and manifestations of the disease may return to pretreatment levels after 6–7 years of levodopa therapy.^{2 6 8 11 53 57 65 66 89} 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 hydrochloride 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}

In clinical studies used to establish efficacy, 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 parkinsonism syndrome that included levodopa/carbidopa, addition of selegiline 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 54 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 54 55 56 66 73}

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 who were receiving optimum antiparkinsonian therapy, addition of selegiline allowed an average reduction in levodopa dosage of 10–30%.^{1 2 5 6 7 34 38 40}

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

Levodopa may be used in conjunction with amantadine, a dopamine agonist (e.g., pramipexole, bromocriptine, pergolide, ropinirole), or anticholinergic agents in the management of parkinsonian syndrome.^{7 8 11 57 65} Whether concomitant administration of selegiline is more effective than other adjunctive agents in parkinsonian patients receiving levodopa has not been determined.^{7 57} Limited evidence indicates that adjuvant therapy with selegiline is as effective as bromocriptine or methixene in the management of parkinsonian syndrome; in these studies, selegiline therapy was better tolerated than bromocriptine or methixene therapy.^{7 52} Therapy with levodopa, selegiline hydrochloride, 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 hydrochloride has been used in a limited number of patients with neuroleptic-induced extrapyramidal manifestations†; selegiline 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} Levodopa is currently the most effective drug for relieving manifestations of parkinsonian syndrome and is considered by many clinicians to be the drug of choice for the management of idiopathic parkinsonian syndrome.¹³⁰ Most clinicians delay introduction of symptomatic therapy until the patient begins to experience functional limitations.¹³⁰ Because levodopa tends to be less effective with prolonged use,^{5 7 57} some clinicians initiate therapy with selegiline, amantadine, or a dopamine agonist.^{8 11 37 57 65 130} 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.^{1 115 117} 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 insitutionalization, 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}

Dosage and Administration

Administration

Selegiline hydrochloride is administered orally, usually in 2 equally divided doses daily.^{1 2 5 6 11} To avoid interference with sleep, selegiline usually is administered with breakfast and lunch.^{1 2 8 11} In patients receiving concomitant levodopa/carbidopa, an attempt to reduce the dosage of levodopa/carbidopa may be made after 2–3 days of selegiline therapy.^{1 2} A reduction in levodopa dosage of at least 10–30% may be needed if dyskinesias develop during selegiline therapy.^{1 2} Further reduction in the dosage of levodopa/carbidopa may be possible during continued selegiline therapy.^{1 2}

Dosage

For the management of parkinsonian syndrome, the usual dosage of selegiline hydrochloride in adults is 5 mg twice daily.^{1 2 5 6 11} Some clinicians suggest an initial selegiline hydrochloride dosage of 2.5 mg daily in patients receiving concomitant levodopa/carbidopa;¹²² dosage may be increased gradually to a maximum of 5 mg twice daily.⁸ The manufacturers state that dosages exceeding 10 mg daily do not result in further improvement in parkinsonian manifestations and are associated with increases in certain adverse effects, including adverse effects associated with nonselective inhibition of monoamine oxidase.^{1 2} Therefore, the manufacturers state that dosages exceeding 10 mg daily generally are not recommended for parkinsonian syndrome.^{1 2}

Cautions

In therapeutic dosage, selegiline hydrochloride generally is well tolerated.^{2 5 39 40 49 50 53 54 55 64 66 67} Many of the adverse effects in patients receiving selegiline hydrochloride 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} 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, discontinuance of selegiline 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}

Nervous System and Muscular Effects

In patients receiving levodopa, addition of selegiline hydrochloride may exacerbate levodopa-associated dyskinesias.^{1 2 5 49 50 64 66 68} This effect, which occurred in an average of 28% (range: 4–90%) of patients receiving the drug in clinical trials, usually occurs within 2 weeks after initiating selegiline therapy^{5 6} and generally is mitigated when the levodopa dosage is reduced (e.g., by 10–30%).^{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} 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 cramping^{1 2} may occur in patients receiving selegiline.^{1 2} Bruxism,^{1 2} muscle twitching^{1 2} and myoclonic jerks^{1 2} have occurred in patients receiving levodopa and selegiline hydrochloride dosages exceeding 10 mg daily.^{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} headache^{1 2 5 50} (including migraine),^{1 2} anxiety,^{1 2 12 50} depression,^{1 2} delusions,^{1 2 50} apathy,^{1 2} psychosis/behavior/mood changes,^{1 2 5 50 66 75} 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 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

Nausea^{1 2 5 6 39 50 66} has been reported in 20%,¹ abdominal pain^{1 2 39 50} in 8%,¹ and dry mouth^{1 2 50} in 6%¹ 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} constipation,^{1 2} and diarrhea^{1 2 50} occur 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 arrhythmias^{1 2} (including tachycardia^{1 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 pectoris^{1 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) of selegiline hydrochloride in association with ingestion of tyramine-containing foods or a sympathomimetic drug.¹ (See Drug Interactions: Food and also Sympathomimetic Agents.)

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 dysfunction^{1 2} have occurred in patients receiving selegiline. Adverse events reported in patients receiving selegiline hydrochloride dosages exceeding 10 mg daily include transient anorgasmia^{1 2} and decreased penile sensation.^{1 2}

Other Adverse Effects

Generalized ache,^{1 2} back pain,^{1 2 50} leg pain,^{1 2} and supraorbital pain^{1 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

Precautions and Contraindications

Because of the risk of adverse effects associated with nonselective inhibition of monoamine oxidase (i.e., inhibition of both monoamine oxidase-A and monoamine oxidase-B), the manufacturers state that selegiline hydrochloride dosages exceeding 10 mg daily generally are not recommended^{1 2} (see Pharmacology), and patients receiving the drug should be advised not to exceed this recommended dosage.^{1 2} In addition, patients should be advised of the risk of serious adverse effects, including hypertensive reaction (i.e., cheese reaction), at selegiline hydrochloride dosages exceeding 10 mg daily.^{1 2} Because such reactions rarely have occurred even at recommended dosages of the drug when tyramine-containing foods or a sympathomimetic drug were used concomitantly, patients should be warned of this possibility (see Drug Interactions: Food and also Sympathomimetic Drugs) and to contact their physician 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 levodopa dosage by 10–30%.^{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}

Selegiline hydrochloride is contraindicated in patients who are hypersensitive to the drug.^{1 2} The drug also is contraindicated in patients receiving meperidine, and possibly in patients receiving other opiates.^{1 2} (See Drug Interactions: Opiate Agonists.) The manufacturers state that selegiline should be avoided in patients receiving or having received recently (i.e., within 5 weeks) fluoxetine therapy.^{1 2} (See Drug Interactions: Antidepressant Agents.) The manufacturers also state that selegiline should be avoided in patients receiving tricyclic antidepressant agents^{1 2} (see Drug Interactions: Antidepressant Agents) and should not be administered concomitantly with nonselective monoamine oxidase inhibitors.^{1 2}

Pediatric Precautions

Safety and efficacy of selegiline in children have not been established.¹

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}

The manufacturers state that following administration of a single 10-mg dose of selegiline hydrochloride 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

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}

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}

Fertility

The effect of selegiline on fertility has not been evaluated.^{1 2}

Lactation

It is not known whether selegiline hydrochloride is distributed into milk.^{1 2} The manufacturers state that consideration should be given to discontinuing the use of all but absolutely essential drug therapy in nursing women.^{1 2}

Drug Interactions

Food

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 selegiline hydrochloride in the dosage recommended for parkinsonian syndrome (i.e., 10 mg daily),^{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 dosage; therefore, caution should be exercised whenever selegiline is used regardless of dosage.¹

At dosages exceeding 10 mg daily, selectivity of selegiline hydrochloride for MAO-B diminishes, the drug will inhibit both MAO-B and MAO-A, and the likelihood of hypertensive reactions increases.^{1 2 5 9 10 11 12 113} Because of the increased risk of a hypertensive reaction at dosages exceeding 10 mg daily, patients with parkinsonian syndrome should be advised not to exceed the recommended dosage of 10 mg daily.^{1 2} Patients receiving selegiline hydrochloride should be instructed to avoid foods and beverages with a high tyramine content, particularly at dosages exceeding 10 mg daily.^{5 9 10 12 32} However, they also should be advised that rare cases of hypertensive reactions have been reported even at the usual dosage of 10 mg daily as a result of dietary indiscretion with tyramine-containing foods.¹ Specialized references on food constituents or a dietician should be consulted for specific information on the tyramine content of foods and beverages.¹²²

Opiate Agonists

Severe agitation, hallucinations, and death have occurred following administration of meperidine in some patients receiving an MAO inhibitor.^{1 2 21 112 118} Stupor, delirium, agitation, muscle rigidity, sweating, and hyperpyrexia occurred in one patient receiving meperidine, selegiline, tricyclic antidepressants, hydroxyzine, pergolide, and levodopa/carbidopa; manifestations resolved over 4–5 days following discontinuance of meperidine and selegiline.^{1 2 5 19 20 112 118} Pending accumulation of additional data clarifying this potentially serious interaction,¹¹⁸ meperidine should not be used in patients receiving selegiline.^{1 2 5 19 21} 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 to interact with selegiline than meperidine, the safety of opiate use in general remains to be established for patients receiving selegiline.^{118 122}

Antidepressant Agents

Serotonergic Agents

Concomitant administration of highly serotonergic drugs (e.g., selective serotonin reuptake inhibitors, 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} (See Drug Interactions: Drugs Associated with Serotonin Syndrome in Fluoxetine 28:16.04.20.) However, available information indicates that serious adverse experiences resulting from combined use of selegiline and an antidepressant agent in patients with parkinsonian syndrome are rare.^{122 126}

Concomitant administration of selegiline and selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) generally should be avoided.^{1 2 17 99 100 101} Because both fluoxetine and its principal metabolite have relatively long half-lives, the manufacturers of selegiline and the manufacturer of fluoxetine recommend that at least 5 weeks elapse between discontinuance of fluoxetine therapy 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} Administration of an MAO inhibitor prior to elapse of at least 5 weeks after discontinuance of fluoxetine may increase the risk of serious adverse effects.^{1 2 17} At least 2 weeks should elapse following discontinuance of other selective serotonin-reuptake inhibitors (i.e., fluvoxamine, paroxetine, sertraline) therapy prior to initiation selegiline.^{99 100 101} In addition, based on clinical experience with concurrent administration of tricyclic antidepressants and MAO inhibitors, the manufacturers of selegiline and the manufacturers of the selective serotonin-reuptake inhibitors recommend that at least 2 weeks elapse following discontinuance of an MAO inhibitor prior to initiation of therapy with a selective serotonin-reuptake inhibitor.^{1 2 17 99 100 101}

The manufacturers state that, in general, concomitant administration of selegiline and tricyclic antidepressants should be avoided.^{1 2} In addition, the manufacturers recommend that at least 2 weeks elapse following discontinuance of selegiline prior to initiation of tricyclic antidepressant therapy.^{1 2} At least 2 weeks also should elapse following discontinuance of tricyclic antidepressant therapy prior to initiation of selegiline therapy.^{102 103}

Other Drugs

Although some patients appear to be sensitive to the hypertensive effects of sympathomimetic agents during therapy with a nonselective MAO inhibitor, nonprescription (over-the-counter, OTC) or prescription cold or hay fever preparations that contain pressor agents (e.g., ephedrine, phenylpropanolamine) generally can be given to patients receiving selegiline hydrochloride dosages of 10 mg or less daily without undue risk of uncontrolled hypertension.^{1 2 5} However, hypertensive crisis was reported in at least one patient receiving the recommended 10-mg daily dosage of selegiline hydrochloride and a sympathomimetic agent (ephedrine).^{1 2}

In a limited number of healthy individuals who received a single 10-mg oral dose of selegiline hydrochloride and a total IV cocaine dose of 60 mg, selegiline did not appear to interact adversely with cocaine.¹¹⁴

Because specific drug interaction studies involving selegiline hydrochloride and other drugs have not been conducted to date and clinical experience with the drug is limited, the possibility of additional drug interactions such as those reported with nonselective MAO inhibitors should be considered.¹

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 overdose of selegiline hydrochloride.^{1 2} At dosages exceeding 10 mg daily, the selectively of selegiline hydrochloride for monoamine oxidase-B (MAO-B) usually diminishes, and the drug will inhibit both MAO-A and MAO-B.^{1 2 7} 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} (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 overdose 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} (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}

Low dosages of selegiline hydrochloride (i.e., 10 mg daily) selectivity inhibit cerebral MAO-B while having little effect on MAO-A in the GI tract and liver.^{1 2 4 5 22 32 84} MAO-A in intestinal tissue is approximately 1000 times less sensitive to inhibition by selegiline than platelet MAO-B.⁴⁴ At high dosages (e.g., exceeding 30 mg daily), 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}

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 mechansims 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 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.^{1 2 4 5 22 23 43 78 79 80 81 82 83 84 85}

Whether 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.^{1 2 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 is 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 bioavailabiliy of 10% has been reported for selegiline hydrochloride tablets.¹⁰⁸ The relative oral bioavailability of selegiline hydrochloride tablets versus oral solution is 76%.¹⁰⁸ Presence of food in the GI tract increases oral bioavailability of selegiline 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, 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 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.^{1 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}

In healthy adults, platelet MAO-B activity was inhibited by 90% following oral administration of selegiline hydrochloride 10 mg 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

Distribution of selegiline hydrochloride into human body tissues and fluids has not been fully characterized.^{1 2} 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 for 3–18 days prior to death.^{2 5 30 44} CSF concentrations of l-desmethylselegiline, l-methamphentamine, and l-amphetamine were 0.7, 14.2, and 6.3 ng/mL, respectively, following long-term administration of selegiline hydrochloride 10 mg daily in a limited number of patients with parkinsonian syndrome.^{32 44} CSF concentrations ofl-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-mediated oxygenation, 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} 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,^{1 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 lamphetamine 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 1.2–2 hours for selegiline has been reported following administration of a single oral 10-mg dose,^{1 87 108} and a half-life of about 10 hours has been reported at steady state with a dosage of 10 mg daily.^{1 108} 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.^{1 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-demethylselegiline.^{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 propynylphenethylamine^{1 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.^{1 2} The drug has a pK_a of 7.5.¹⁰⁹

Stability

Commercially available selegiline hydrochloride capsules and tablets should be stored at 15–30°C.^{1 2}

Preparations

Selegiline Hydrochloride

Routes	Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	5 mg*	Eldepryl®	Somerset
	Tablets	5 mg*	Selegiline Hydrochloride Tablets	Apotex, Endo, Teva

* available by nonproprietary name

Comparative Pricing

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