Eldepryl

Generic Name: Selegiline Hydrochloride
Class: Monoamine Oxidase B Inhibitors
VA Class: CN500
Chemical Name: (R)-N,α-Dimethyl-N-2-propynyl-benzeneethanamine hydrochloride
Molecular Formula: C13H17N•ClH
CAS Number: 14611-52-0

Introduction

Relatively selective MAO-B inhibitor.1 2 3

Uses for Eldepryl

Parkinsonian Syndrome

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

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

Alzheimer’s Disease

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

Eldepryl Dosage and Administration

General

Concomitant Levodopa/Carbidopa Therapy

  • In patients receiving concomitant levodopa/carbidopa, an attempt to reduce levodopa/carbidopa dosage may be made after 2–3 days of selegiline therapy.1 2

  • Reduction in levodopa dosage of 10–30% may be needed if dyskinesias develop during selegiline therapy.1 2

  • Further reduction in levodopa/carbidopa dosage may be possible during continued selegiline therapy.1 2

Administration

Oral Administration

Administer orally, usually in 2 equally divided doses daily1 2 5 6 11 (generally at breakfast and lunch to avoid interference with sleep1 2 8 11 ).

Dosage

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

Adults

Parkinsonian Syndrome
Oral

Usual dosage: 5 mg twice daily.1 2 5 6 11

Some clinicians suggest an initial dosage of 2.5 mg daily in patients receiving concomitant levodopa/carbidopa;122 may increase dosage gradually up to 5 mg twice daily.8

Prescribing Limits

Adults

Parkinsonian Syndrome
Oral

Maximum 10 mg daily.1 (See Risks Associated with MAO Inhibition under Cautions.)

Special Populations

No special population dosage recommendations.1

Cautions for Eldepryl

Contraindications

  • Known hypersensitivity to selegiline or any ingredient in the formulation.1 2

  • Concomitant administration of meperidine and possibly other opiates.1 2 (See Specific Drugs and Foods under Interactions.)

Warnings/Precautions

Warnings

Risks Associated with MAO Inhibition

Selectivity for MAO-B is relative.1 2 3 At dosage of 10 mg daily, selegiline hydrochloride inhibits cerebral MAO-B while having little effect on MAO-A in the GI tract and liver.1 2 4 5 22 32 84 At high dosages (e.g., 30–40 mg daily), the selectivity usually diminishes and the drug will inhibit MAO-B and MAO-A.1 2 4 5 22 32

Hypertensive crises following ingestion of foods containing large amounts of tyramine (i.e., cheese reaction) have occurred in patients receiving nonselective MAO inhibitors.123 Hypertensive reactions reported rarely in patients receiving selegiline hydrochloride 10 mg daily (the maximum recommended dosage);1 at dosages >10 mg daily, the likelihood of hypertensive reactions increases.1 2 5 9 10 11 12 113 Use selegiline with caution regardless of the dosage.1 (See Interactions and also Advice to Patients.)

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

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

General Precautions

Exacerbation of Levodopa-associated Adverse Effects

Selegiline may exacerbate levodopa-associated adverse effects (e.g., dyskinesias1 2 5 49 50 64 66 68 ), presumably by increasing dopaminergic activity; effects generally can be mitigated by reducing the levodopa dosage by 10–30%.1 2 5 68

Melanoma

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

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

Intense Urges

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

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

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether selegiline is distributed into milk.1 2 Give consideration to discontinuing the use of all but absolutely essential drug therapy in nursing women.1 2

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

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

Common Adverse Effects

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

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

Interactions for Eldepryl

The possibility of interactions such as those reported with nonselective MAO inhibitors should be considered.1

Interactions Involving Nonselective MAO Inhibitors

Some patients appear to be sensitive to the hypertensive effects of sympathomimetic agents during therapy with a nonselective MAO inhibitor.1 2 5

Hypertensive crises following ingestion of foods containing large amounts of tyramine (i.e., cheese reaction) have occurred in patients receiving nonselective MAO inhibitors.123

Concomitant use of highly serotonergic drugs and MAO inhibitors is potentially hazardous and may result in serotonin syndrome.1 2 13 16 17 97 99 100 101 112 (See Risks Associated with MAO Inhibition under Cautions.)

Severe agitation, hallucinations, and death have occurred following administration of meperidine in some patients receiving an MAO inhibitor.1 2 21 112 118

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antidepressants, SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline)

Potential for serious, possibly fatal adverse effects resembling serotonin syndrome1 122 126 131

Generally avoid concomitant use1 2 17 99 100 101

Allow ≥2 weeks to elapse between discontinuance of an MAO inhibitor and initiation of an SSRI1 2 17 99 100 101

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

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

Antidepressants, tricyclics (e.g., amitriptyline, protriptyline)

Potential for serious, possibly fatal adverse effects resembling serotonin syndrome1 122 126 131

Generally avoid concomitant use of selegiline and tricyclic antidepressants1 2

Allow ≥2 weeks to elapse between discontinuance of selegiline and initiation of a tricyclic antidepressant,1 2 or vice versa102 103

Foods, tyramine-containing

Hypertensive reactions reported rarely at selegiline hydrochloride dosage of 10 mg daily;1 increased risk of hypertensive reactions at dosages >10 mg daily1 2 5 9 10 11 12 113

Limit selegiline hydrochloride dosage to 10 mg daily1 2

Exercise caution regardless of the dosage;1 avoid foods and beverages with high tyramine content, particularly at dosages >10 mg daily5 9 10 12 32

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

Levodopa

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

Reduction of levodopa dosage by 10–30% may mitigate adverse effects1 2 5 68

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

MAO inhibitors, nonselective

Avoid concomitant use132

Opiate agonists

Stupor, muscular rigidity, severe agitation, and elevated temperature reported in some patients receiving meperidine with selegiline; resolution usually occurs over several days following discontinuance of both drugs1 2 5 19 20 112 118

Interaction theoretically less likely with morphine; however, the safety of concomitant opiate use in general remains to be established 118 122

Concomitant use with meperidine is contraindicated;1 2 5 19 21 consider discontinuing selegiline 2 weeks prior to scheduled surgery if postoperative meperidine analgesia is possible112

Concomitant use with other opiate agonists also may be contraindicated1 2

Sympathomimetic agents (e.g., ephedrine)

Hypertensive crisis reported in at least one patient receiving selegiline hydrochloride 10 mg daily and ephedrine1 2

Cold or hay fever preparations containing pressor agents (e.g., ephedrine) generally can be given to patients receiving selegiline hydrochloride dosages of ≤10 mg daily without undue risk of uncontrolled hypertension1 2 5

Eldepryl Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak plasma selegiline concentrations achieved within 0.5–0.9 hours in fasting individuals.86 87 108 110

Undergoes extensive first-pass metabolism in the gut wall and liver.1 32 108 Oral bioavailability of 10% reported for selegiline hydrochloride tablets.108

Following single oral 10-mg dose, peak plasma concentrations of the first-pass metabolites (l-desmethylselegiline, l-methamphetamine, and l-amphetamine) are 3- to 20-fold higher than the peak plasma concentrations of selegiline.1 108 110 At steady-state, peak plasma selegiline and metabolite concentrations are increased 2.6- to 4-fold and 1.5- to 2-fold, respectively, compared with values following a single dose.1 108

Food

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

Special Populations

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

Distribution

Extent

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

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

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

Plasma Protein Binding

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

Elimination

Metabolism

Extensively metabolized, principally in the gut wall and liver, to l-desmethylselegiline and l-methylamphetamine (CYP-mediated) and then to l-amphetamine.1 32 108 The amphetamine metabolites may be hydroxylated and then conjugated with glucuronic acid.5 32 88 108

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

Elimination Route

Excreted principally in urine as conjugated and unconjugated metabolites1 5 12 26 27 28 29 30 31 32 44 (20–63% as l-methamphetamine, 9–26% as l-amphetamine, and 1% as l-desmethylselegiline5 12 31 44 ).

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

Half-life

Selegiline: 1.2–2 hours (single oral 10-mg dose);1 87 108 about 10 hours (at steady state with a dosage of 10 mg daily).1 108

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

Stability

Storage

Oral

Capsules and Tablets

20–25°C.1 2

Actions

  • Relatively selective MAO-B inhibitor.1 2 3 At dosage of 10 mg daily, selegiline hydrochloride inhibits cerebral MAO-B while having little effect on MAO-A in the GI tract and liver.1 2 4 5 22 32 84 At high dosages (e.g., 30–40 mg daily), the selectivity usually diminishes and the drug will inhibit MAO-B and MAO-A.1 2 4 5 22 32

  • Principal physiologic action in the management of parkinsonian syndrome is irreversible inhibition of MAO-B within the nigrostriatal pathways in the CNS,1 2 4 5 22 thereby blocking microsomal metabolism of dopamine 1 2 4 5 22 and enhancing dopaminergic activity in the substantia nigra.1 2 4 5 22 Reduces the amount of levodopa required to maintain optimum dopamine concentrations in the brain of patients with parkinsonian syndrome.1 2 4 5 22

  • May increase dopaminergic activity by mechanisms other than MAO-B inhibition (e.g., interference with dopamine reuptake at the synapse).1 2 5 84

  • 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

  • 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 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 release of dopamine from intact neurons and also to block activation of N-methyl-d-aspartate (NMDA)-sensitive glutamate receptors may contribute to selegiline’s activity.1 2 4 5 22 23 43 78 79 80 81 82 83 84 85

Advice to Patients

  • Risk of serious adverse effects (e.g., hypertensive reactions) at dosages >10 mg daily.1 2 Importance of not exceeding the recommended dosage.1 2

  • Advise patient that serious adverse reactions (e.g., hypertensive reactions) rarely have occurred even at the recommended dosage when tyramine-containing foods or a sympathomimetic drug was used concomitantly.1 2 122 Importance of avoiding foods and beverages with a high tyramine content, particularly if dosage >10 mg daily is used.5 9 10 12 32

  • Importance of contacting clinician if signs or symptoms of hypertension (e.g., headache, neck stiffness or soreness, palpitation) or other unusual symptoms occur.1 2 122

  • Potential for selegiline to exacerbate levodopa-associated adverse effects (e.g., dyskinesias).1 2 5 68 Possible need for reduction of levodopa dosage following initiation of selegiline.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

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

Selegiline Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

5 mg*

Eldepryl

Somerset

Selegiline Hydrochloride Capsules

Tablets

5 mg*

Selegiline Hydrochloride Tablets

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Eldepryl 5MG Capsules (SOMERSET PHARM): 60/$158.00 or 180/$452.98

Selegiline HCl 5MG Capsules (DAVA PHARMACEUTICALS): 60/$110.99 or 180/$312.99

Selegiline HCl 5MG Tablets (MYLAN): 30/$60.99 or 90/$165.98

Zelapar 1.25MG Dispersible Tablets (VALEANT): 10/$99.99 or 30/$295.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions April 19, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

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