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
Brands: Eldepryl

Special Alerts:

[Posted 05/02/2007] FDA notified healthcare professionals that the Agency proposed that makers of all antidepressant medications update the existing black box warning on the prescribing information for their products to include warnings about the increased risks of suicidal thinking and behavior in young adults ages 18 to 24 years old during the first one to two months of treatment. The proposed labeling changes also state that scientific data did not show this increased risk in adults older than 24 years of age and that adults 65 years of age and older taking antidepressants have a decreased risk of suicidality. The proposed updates apply to the entire category of antidepressants. Individuals currently taking prescribed antidepressant medications should not stop taking them and should notify their healthcare professional if they have concerns. Manufacturers of antidepressant medications will have 30 days to submit their revised product labeling and revised Medication Guides to FDA for review. See the FDA press release for the list of products affected by the proposed antidepressant product labeling changes. For more information visit the FDA website at: , and .

Introduction

Relatively selective MAO-B inhibitor.^{1 2 3}

Uses for Selegiline Hydrochloride

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Parkinsonian Syndrome

Symptomatic treatment of parkinsonian syndrome; designated an ophan drug by FDA for this condition.^{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}

Used as adjunctive therapy in parkinsonian patients who exhibit a deteriorating response to levidopa/carbidopa.^{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} Epecially useful in improving “end-of-dose” motor fluctuations.^{5 6 7 49 51 85}

Has been used effectively 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 syndrome^{3 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}

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}

Selegiline Hydrochloride Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 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 at least 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 daily^{1 2 5 6 11} (generally at breakfast and lunch to avoid interference with sleep^{1 2 8 11} ).

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Adults

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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 Selegiline Hydrochloride

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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 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} Generally avoid concomitant use.^{1 2} (See Interactions.)

Because of the complexitiy 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., dyskinesias^{1 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}

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 have not been 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 Selegiline Hydrochloride

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 (e.g., SSRIs, tricyclic antidepressants) and MAO inhibitors is potentially hazardous and may result in serotonin syndrome.^{1 2 13 16 17 97 99 100 101 112}

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)	Serious, sometimes fatal adverse effects (e.g., hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations of vital signs, extreme agitation, delirium, coma) reported rarely1 122 126	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 in patients who received 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)	Serious, sometimes fatal adverse effects (e.g., hypertension, syncope, asystole, diaphoresis, seizures, mental status and behavioral changes, muscular rigidity, tremors, agitation, restlessness, unresponsiveness) reported rarely122 126	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 use1 2
Opiate agonists	Stupor, agitation, muscular rigidity, and elevated temperature reported in patients receiving meperidine with selegiline; resolution usually occurs over 4–5 days following discontinuance of the drugs1 2 5 19 20 112 118	Concomitant use of meperidine is contraindicated;1 2 5 19 21 consider discontinuing selegiline 2 weeks prior to scheduled surgery if postoperative meperidine analgesia is possible112 Morphine theoretically would be less likely to interact with selegiline; however, the safety of opiate use in general remains to be established for patients receiving selegiline118 122
Sympathomimetic agents (e.g., ephedrine, phenylpropanolamine)	Hypertensive crisis reported in at least 1 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

Selegiline Hydrochloride 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 barrier^{1 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 metabolites^{1 5 12 26 27 28 29 30 31 32 44} (20–63% as l-methamphetamine, 9–26% as l-amphetamine, and 1% as l-desmethylselegiline^{5 12 31 44} ).

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

Half-life

Selegiline: 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

15–30°C.^{1 2}

ActionsActions

• 
  

  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 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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  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
	Tablets	5 mg*	Selegiline Hydrochloride Tablets	Apotex, Endo, Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. 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/$170 or 180/$490.01

Selegiline HCl 5MG Capsules (DAVA PHARMACEUTICALS): 60/$101.99 or 180/$285.95

Zelapar 1.25MG Dispersible Tablets (VALEANT): 30/$269.78 or 60/$533.18

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions April 2010. 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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