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Selegiline

Pronunciation

Pronunciation

(se LE ji leen)

Index Terms

  • Deprenyl
  • L-Deprenyl
  • Selegiline HCl
  • Selegiline Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Eldepryl: 5 mg

Generic: 5 mg

Patch 24 Hour, Transdermal:

Emsam: 6 mg/24 hr (30 ea); 9 mg/24 hr (30 ea); 12 mg/24 hr (30 ea)

Tablet, Oral, as hydrochloride:

Generic: 5 mg

Tablet Dispersible, Oral, as hydrochloride:

Zelapar: 1.25 mg [contains aspartame; grapefruit flavor]

Brand Names: U.S.

  • Eldepryl
  • Emsam
  • Zelapar

Pharmacologic Category

  • Anti-Parkinson Agent, MAO Type B Inhibitor
  • Antidepressant, Monoamine Oxidase Inhibitor

Pharmacology

Potent, irreversible inhibitor of monoamine oxidase (MAO). Plasma concentrations achieved via administration of oral dosage forms in recommended doses confer selective inhibition of MAO type B, which plays a major role in the metabolism of dopamine, serotonin, norepinephrine, and epinephrine in the CNS; selegiline may also increase dopaminergic activity by interfering with dopamine reuptake at the synapse. When administered transdermally in recommended doses, selegiline achieves higher blood levels and effectively inhibits both MAO-A and MAO-B, an enzyme in the gut and liver that metabolizes dietary amines such as tyramine.

Absorption

Capsule/tablet: Bioavailability increases 3- to 4-fold when taken with food

Orally disintegrating tablet: Rapid; greater bioavailability than capsule/tablet. Food decreases Cmax and AUC to ~60% of fasting state.

Transdermal: 25% to 30% (of total selegiline content) over 24 hours

Metabolism

Hepatic, primarily via CYP2B6, CYP2C9, CYP3A4, and CYP2A6 (minor) to active (N-desmethylselegiline, amphetamine, methamphetamine) and inactive metabolites

Excretion

Urine (primarily metabolites); feces

Half-Life Elimination

Oral: 10 hours

Protein Binding

Protein binding: 85% to 90%

Special Populations: Renal Function Impairment

Orally disintegrating tablets: Patients with moderate renal impairment (CrCl 31 to 50 mL/minute) had a 34% to 67% increase in exposure to the active metabolites methamphetamine and amphetamine. Patients with end-stage renal disease off dialysis had a 4-fold increase in exposure to the active metabolites methamphetamine and amphetamine.

Special Populations: Hepatic Function Impairment

Orally disintegrating tablets: Patients with mild hepatic impairment (Child-Pugh score 5 to 6) had a 1.5-fold higher AUC and Cmax of selegiline and a 1.4-fold and 1.2-fold higher, respectively, AUC and Cmax of the metabolite desmethylselegiline. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), AUC of selegiline and desmethylselegiline increased 1.5-fold and 1.8-fold, respectively. Patients with severe hepatic impairment (Child-Pugh score >9) had a 4-fold increased AUC of selegiline, 3-fold increased Cmax of selegiline, 1.25-fold increased AUC of desmethylselegeline and 50% reduced Cmax of desmethylselegeline.

Special Populations: Elderly

Systemic exposure is about twice as high in elderly patients when given a single 10 mg oral dose.

Use: Labeled Indications

Parkinson disease: Adjunct in the management of patients with Parkinson disease being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy (oral products).

Major depressive disorder: Treatment of major depressive disorder (MDD) (transdermal patch)

Use: Unlabeled

Early Parkinson's disease; attention-deficit/hyperactivity disorder (ADHD)

Contraindications

Hypersensitivity to selegiline or any component of the formulation; concomitant use of meperidine

Orally disintegrating tablet: Additional contraindications: Concomitant use of methadone, other MAO inhibitors (selective or non-selective), propoxyphene, or tramadol within 14 days of selegiline; concomitant use with cyclobenzaprine, dextromethorphan, or St John’s wort

Transdermal: Additional contraindications: Pheochromocytoma; patients <12 years of age; use of carbamazepine, serotonin reuptake inhibitors (including SSRIs and SNRIs), clomipramine, imipramine, tramadol, propoxyphene, methadone, pentazocine, and dextromethorphan (concurrently, within 2 weeks of selegiline discontinuation, or selegiline use within 4 to 5 half-lives [approximately 1 week for most medications; 5 weeks for fluoxetine] of discontinuation of the contraindicated drug)

Dosing: Adult

Depression: Transdermal: Initial: 6 mg/24 hours once daily; target dose: 6 mg/24 hours once daily; may titrate based on clinical response in increments of 3 mg/day every 2 weeks up to a maximum of 12 mg/24 hours

Parkinson disease:

Capsule, tablet: 5 mg twice daily with breakfast and lunch with concomitant carbidopa/levodopa therapy; maximum: 10 mg/day.

Orally disintegrating tablet: Initial: 1.25 mg once daily with concomitant carbidopa/levodopa therapy for at least 6 weeks; may increase to 2.5 mg once daily based on clinical response and tolerability (maximum: 2.5 mg/day).

Concomitant therapy with carbidopa/levodopa: After 2 to 3 days, an attempt may be made to reduce the dose of levodopa/carbidopa by 10% to 30%. Further reductions of levodopa/carbidopa may be possible during continued selegiline therapy.

Discontinuation of therapy: Upon discontinuation of antidepressant or antiparkinsonian therapy, gradually taper the dose to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms. Evidence supporting ideal taper rates is limited. APA and NICE depression guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life and MAO inhibitors may need to be tapered more conservatively. In addition for long-term treated patients, WFSBP guidelines recommend tapering over 4 to 6 months. If intolerable withdrawal symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (APA 2010; Bauer 2002; Haddad 2001; NCCMH 2010; Schatzberg 2006; Shelton 2001; Warner 2006).

MAO inhibitor recommendations:

Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

Allow 14 days (or a time equal to 4 to 5 half-lives of the drug) to elapse between discontinuing an alternative antidepressant without long half-life metabolites (eg, TCAs, paroxetine, fluvoxamine, venlafaxine) or MAO inhibitor intended to treat psychiatric disorders and initiation of selegiline (APA [Gelenberg 2010]).

Allow 5 weeks to elapse between discontinuing fluoxetine (with long half-life metabolites) intended to treat psychiatric disorders and initiation of selegiline.

Allow 14 days to elapse between discontinuing selegiline and initiation of an alternative antidepressant or MAO inhibitor intended to treat psychiatric disorders.

Dosing: Geriatric

Parkinson disease:

Capsule, tablet: ≤5 mg/day (when combined with levodopa) is recommended by some clinicians to decrease the enhanced dopaminergic side effects (Olanow 2001).

Orally disintegrating tablet: Refer to adult dosing.

Depression: Transdermal: 6 mg/24 hours once daily

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.

Dosing: Pediatric

Depression: Adolescents >17 years: Transdermal: Refer to adult dosing.

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.

Dosing: Renal Impairment

Oral:

Capsules, tablets: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Use with caution.

Orally disintegrating tablet:

CrCl 30 to 89 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Use is not recommended.

End-stage renal disease: Use is not recommended.

Transdermal:

eGFR ≥15 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

ESRD requiring dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Oral:

Capsules/tablets: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Use with caution.

Orally disintegrating tablet:

Mild to moderate impairment (Child-Pugh class A and B): 1.25 mg once daily based on clinical response and tolerability.

Severe impairment (Child-Pugh class C): Use is not recommended.

Transdermal:

Mild to moderate impairment (Child-Pugh class A and B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Administration

Oral: Orally disintegrating tablet: Remove tablet from pouch immediately before administering. Administer in morning before breakfast; do not swallow; place on top of tongue and allow to dissolve. Avoid food or liquid 5 minutes before and after administration.

Topical: Transdermal: Apply to clean, dry, intact skin to the upper torso (below the neck and above the waist), upper thigh, or outer surface of the upper arm. Do not apply to skin that is hairy, oily, irritated, broken, scarred, or calloused. Do not place under tight clothing. Apply at the same time each day and rotate application sites. Wash hands with soap and water after handling. Avoid touching the sticky side of the patch. Discard any used or unused patches by folding adhesive ends together and discard properly in trash.

Dietary Considerations

Avoid or limit tyramine-containing foods/beverages (product and/or dose-dependent). Some examples include aged or matured cheese, air-dried or cured meats (including sausages and salamis), fava or broad bean pods, tap/draft beers, Marmite concentrate, sauerkraut, soy sauce and other soybean condiments. Food’s freshness is also an important concern; improperly stored or spoiled food can create an environment where tyramine concentrations may increase.

Transdermal: 9 mg/24 hours or 12 mg/24 hours: Avoid tyramine-rich foods or beverages beginning the first day of treatment and for 2 weeks after discontinuation or dose reduction to 6 mg/24 hours.

Orally disintegrating tablet: Do not take with food or liquid.

Some products may contain phenylalanine.

Storage

Capsule, tablet, transdermal: Store at 20°C to 25°C (68°F to 77°F). Store patch in sealed pouch and apply immediately after removal. Protect capsule and tablet from light.

Orally disintegrating tablet: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Use within 3 months of opening pouch and immediately after opening individual blister.

Drug Interactions

Alcohol (Ethyl): May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alpha-/Beta-Agonists (Indirect-Acting): MAO Inhibitors may enhance the hypertensive effect of Alpha-/Beta-Agonists (Indirect-Acting). While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Avoid combination

Alpha1-Agonists: MAO Inhibitors may enhance the hypertensive effect of Alpha1-Agonists. While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Avoid combination

Altretamine: May enhance the orthostatic hypotensive effect of MAO Inhibitors. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: MAO Inhibitors may enhance the hypertensive effect of Amphetamines. While linezolid and tedizolid may interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): MAO Inhibitors may enhance the adverse/toxic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). While methylene blue and linezolid are expected to interact, specific recommendations for their use differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Apraclonidine: MAO Inhibitors may enhance the adverse/toxic effect of Apraclonidine. MAO Inhibitors may increase the serum concentration of Apraclonidine. Avoid combination

AtoMOXetine: MAO Inhibitors may enhance the neurotoxic (central) effect of AtoMOXetine. Avoid combination

Atropine (Ophthalmic): MAO Inhibitors may enhance the hypertensive effect of Atropine (Ophthalmic). Avoid combination

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta2-Agonists: MAO Inhibitors may enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Betahistine: MAO Inhibitors may increase the serum concentration of Betahistine. Monitor therapy

Bezafibrate: MAO Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Avoid combination

Blood Glucose Lowering Agents: MAO Inhibitors may enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Ophthalmic): MAO Inhibitors may enhance the adverse/toxic effect of Brimonidine (Ophthalmic). MAO Inhibitors may increase the serum concentration of Brimonidine (Ophthalmic). Monitor therapy

Brimonidine (Topical): MAO Inhibitors may enhance the adverse/toxic effect of Brimonidine (Topical). MAO Inhibitors may increase the serum concentration of Brimonidine (Topical). Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Buprenorphine: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

BuPROPion: MAO Inhibitors may enhance the hypertensive effect of BuPROPion. Avoid combination

BusPIRone: May enhance the adverse/toxic effect of MAO Inhibitors. Specifically, blood pressure elevations been reported. Avoid combination

CarBAMazepine: May enhance the adverse/toxic effect of MAO Inhibitors. Management: Avoid concurrent use of carbamazepine during, or within 14 days of discontinuing, treatment with a monoamine oxidase inhibitor. Avoid combination

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of MAO Inhibitors. Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

Codeine: MAO Inhibitors may enhance the adverse/toxic effect of Codeine. Monitor therapy

COMT Inhibitors: May enhance the adverse/toxic effect of MAO Inhibitors. Consider therapy modification

Contraceptives (Estrogens): May increase the serum concentration of Selegiline. Monitor therapy

Contraceptives (Progestins): May increase the serum concentration of Selegiline. Monitor therapy

Cyclobenzaprine: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

CYP2B6 Inducers (Moderate): May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

Cyproheptadine: MAO Inhibitors may enhance the anticholinergic effect of Cyproheptadine. Cyproheptadine may diminish the serotonergic effect of MAO Inhibitors. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Dexmethylphenidate: MAO Inhibitors may enhance the hypertensive effect of Dexmethylphenidate. Avoid combination

Dextromethorphan: MAO Inhibitors may enhance the serotonergic effect of Dextromethorphan. This may cause serotonin syndrome. Avoid combination

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Diethylpropion: MAO Inhibitors may enhance the hypertensive effect of Diethylpropion. Avoid combination

Domperidone: MAO Inhibitors may enhance the adverse/toxic effect of Domperidone. Domperidone may diminish the therapeutic effect of MAO Inhibitors. MAO Inhibitors may diminish the therapeutic effect of Domperidone. Monitor therapy

Doxapram: MAO Inhibitors may enhance the hypertensive effect of Doxapram. Monitor therapy

EPINEPHrine (Nasal): MAO Inhibitors may enhance the hypertensive effect of EPINEPHrine (Nasal). Monitor therapy

EPINEPHrine (Oral Inhalation): MAO Inhibitors may enhance the hypertensive effect of EPINEPHrine (Oral Inhalation). Avoid combination

Epinephrine (Racemic): MAO Inhibitors may enhance the hypertensive effect of Epinephrine (Racemic). Monitor therapy

EPINEPHrine (Systemic): MAO Inhibitors may enhance the hypertensive effect of EPINEPHrine (Systemic). Monitor therapy

FentaNYL: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

HYDROcodone: MAO Inhibitors may enhance the adverse/toxic effect of HYDROcodone. Management: Consider alternatives to this combination when possible. Consider therapy modification

HYDROmorphone: MAO Inhibitors may enhance the adverse/toxic effect of HYDROmorphone. Avoid combination

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Indoramin: MAO Inhibitors may enhance the hypotensive effect of Indoramin. Avoid combination

Ioflupane I 123: Selegiline may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Isometheptene: MAO Inhibitors may enhance the adverse/toxic effect of Isometheptene. Avoid combination

Levodopa: May enhance the adverse/toxic effect of MAO Inhibitors. Of particular concern is the development of hypertensive reactions when levodopa is used with nonselective MAOI. Management: The concomitant use of nonselective monoamine oxidase inhibitors (MAOIs) and levodopa is contraindicated. Discontinue the nonselective MAOI at least two weeks prior to initiating levodopa. Monitor patients taking a selective MAOIs and levodopa. Consider therapy modification

Levonordefrin: MAO Inhibitors may enhance the hypertensive effect of Levonordefrin. Avoid combination

Linezolid: MAO Inhibitors may enhance the adverse/toxic effect of Linezolid. Avoid combination

Lithium: MAO Inhibitors may enhance the adverse/toxic effect of Lithium. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypertensive effect of other MAO Inhibitors. MAO Inhibitors may enhance the serotonergic effect of other MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Maprotiline: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Meperidine: MAO Inhibitors may enhance the serotonergic effect of Meperidine. This may cause serotonin syndrome. Avoid combination

Meptazinol: MAO Inhibitors may enhance the adverse/toxic effect of Meptazinol. Avoid combination

Mequitazine: MAO Inhibitors may enhance the anticholinergic effect of Mequitazine. Avoid combination

Metaraminol: MAO Inhibitors may enhance the hypertensive effect of Metaraminol. Monitor therapy

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methyldopa: MAO Inhibitors may enhance the adverse/toxic effect of Methyldopa. Avoid combination

Methylene Blue: MAO Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Methylphenidate: MAO Inhibitors may enhance the hypertensive effect of Methylphenidate. Avoid combination

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

Mianserin: MAO Inhibitors may enhance the neurotoxic effect of Mianserin. Avoid combination

MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

Mirtazapine: MAO Inhibitors may enhance the neurotoxic (central) effect of Mirtazapine. While methylene blue and linezolid are expected to interact, specific recommendations for their use differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Moclobemide: MAO Inhibitors may enhance the adverse/toxic effect of Moclobemide. Avoid combination

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Morphine (Liposomal): MAO Inhibitors may enhance the adverse/toxic effect of Morphine (Liposomal). Avoid combination

Morphine (Systemic): MAO Inhibitors may enhance the adverse/toxic effect of Morphine (Systemic). Avoid combination

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nefopam: MAO Inhibitors may enhance the adverse/toxic effect of Nefopam. Avoid combination

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nilotinib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Norepinephrine: MAO Inhibitors may enhance the hypertensive effect of Norepinephrine. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

OXcarbazepine: May enhance the serotonergic effect of Selegiline. Avoid combination

OxyCODONE: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Management: Seek alternatives when possible. Avoid use of oxycodone/naltrexone during and within 14 days after monoamine oxidase inhibitor treatment. Non-US labeling for some oxycodone products states that such use is contraindicated. Consider therapy modification

OxyMORphone: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pheniramine: May enhance the anticholinergic effect of MAO Inhibitors. Avoid combination

Pholcodine: May enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pindolol: MAO Inhibitors may enhance the hypotensive effect of Pindolol. Management: Canadian labeling for pindolol states that concurrent use with a monoamine oxidase inhibitor is not recommended. Consider therapy modification

Pipamperone [INT]: Anti-Parkinson Agents (Monoamine Oxidase Inhibitor) may diminish the therapeutic effect of Pipamperone [INT]. Pipamperone [INT] may diminish the therapeutic effect of Anti-Parkinson Agents (Monoamine Oxidase Inhibitor). Monitor therapy

Pizotifen: MAO Inhibitors may enhance the anticholinergic effect of Pizotifen. Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Reboxetine: MAO Inhibitors may enhance the adverse/toxic effect of Reboxetine. Avoid combination

Reserpine: MAO Inhibitors may enhance the adverse/toxic effect of Reserpine. Existing MAOI therapy can result in paradoxical effects of added reserpine (e.g., excitation, hypertension). Management: Monoamine oxidase inhibitors (MAOIs) should be avoided or used with great caution in patients who are also receiving reserpine. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: MAO Inhibitors may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Serotonin 5-HT1D Receptor Agonists: MAO Inhibitors may decrease the metabolism of Serotonin 5-HT1D Receptor Agonists. Management: If MAO inhibitor therapy is required, naratriptan, eletriptan or frovatriptan may be a suitable 5-HT1D agonist to employ. Exceptions: Eletriptan; Frovatriptan; Naratriptan. Avoid combination

Serotonin Modulators: Anti-Parkinson Agents (Monoamine Oxidase Inhibitor) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if selegiline or rasagiline is combined with a serotonin modulator. Use of transdermal selegiline with serotonin modulators is contraindicated. Exceptions: Nicergoline. Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors: MAO Inhibitors may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Tapentadol: May enhance the adverse/toxic effect of MAO Inhibitors. Specifically, the additive effects of norepinephrine may lead to adverse cardiovascular effects. Tapentadol may enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Tetrabenazine: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Tetrahydrozoline (Nasal): MAO Inhibitors may enhance the hypertensive effect of Tetrahydrozoline (Nasal). Avoid combination

Thiotepa: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tricyclic Antidepressants: MAO Inhibitors may enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Tryptophan: May enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Test Interactions

May interfere with urine detection of amphetamine/methamphetamine (false-positive).

Adverse Reactions

Unless otherwise noted, the percentage of adverse events is reported for the transdermal patch (Note: ODT = orally disintegrating tablet, Oral = capsule/tablet)

>10%:

Central nervous system: Headache (18%; ODT 7%; oral 4%), insomnia (12%; ODT 7%), dizziness (oral 14%; ODT 11%)

Gastrointestinal: Nausea (oral 20%; ODT 11%)

Local: Application site reaction (24%)

1% to 10%:

Cardiovascular: Hypotension (including postural 3% to 10%), palpitation (oral 2%), chest pain (≥1%; ODT 2%), hypertension (≥1%; ODT 3%), peripheral edema (≥1%)

Central nervous system: Pain (ODT 8%; oral 2%), hallucinations (oral 6%; ODT 4%), confusion (oral 6%; ODT 4%), vivid dreams (oral 4%), ataxia (ODT 3%), somnolence (ODT 3%), lethargy (oral 2%), agitation (≥1%), amnesia (≥1%), paresthesia (≥1%), thinking abnormal (≥1%), depression (<1%; ODT 2%)

Dermatologic: Rash (4%), bruising (≥1%; ODT 2%), pruritus (≥1%), acne (≥1%)

Endocrine & metabolic: Weight loss (5%; oral 2%), hypokalemia (ODT 2%), sexual side effects (≤1%)

Gastrointestinal: Diarrhea (9%; ODT 2%; oral 2%), xerostomia (8%; oral 6%; ODT 4%), stomatitis (ODT 5%), abdominal pain (oral 8%), dyspepsia (4%; ODT 5%), dysphagia (ODT 2%), dental caries (ODT 2%), constipation (≥1%; ODT 4%), flatulence (≥1%; ODT 2%), anorexia (≥1%), gastroenteritis (≥1%), taste perversion (≥1%; ODT 2%), vomiting (≥1%; ODT 3%)

Genitourinary: Urinary retention (oral 2%), dysmenorrhea (≥1%), metrorrhagia (≥1%), UTI (≥1%), urinary frequency (≥1%)

Neuromuscular & skeletal: Dyskinesia (ODT 6%), back pain (ODT 5%; oral 2%), ataxia (<1%; ODT 3%), leg cramps (ODT 3%; oral 2%), myalgia (≥1%; ODT 3%), neck pain (≥1%), tremor (<1%; ODT 3%)

Otic: Tinnitus (≥1%)

Respiratory: Rhinitis (ODT 7%), pharyngitis (3%; ODT 4%), sinusitis (3%), cough (≥1%), bronchitis (≥1%), dyspnea (<1%; ODT 3%)

Miscellaneous: Diaphoresis (≥1%)

Oral and/or transdermal patch: <1% or frequency not defined (limited to important or life-threatening): Abnormal liver function tests, alkaline phosphatase increased, appetite increased, arrhythmia, asthma, ataxia, atrial fibrillation, bacterial infection, behavior/mood changes, bilirubinemia, bradycardia, bradykinesia, breast neoplasm (female), breast pain, chorea, circumoral paresthesia, colitis, dehydration, delusions, depersonalization, depression, emotional lability, epistaxis, eructation, euphoria, face edema, fever, fungal infection, gastritis, generalized spasm, glossitis, heat stroke, hematuria (female), hernia, hostility, hypercholesterolemia, hyperesthesia, hyperglycemia, hyperkinesias, hypertonia, hypoglycemic reaction, hyponatremia, impulsive/compulsive behaviors (eg, pathological gambling, hypersexuality, binge eating), kidney calculus (female), lactate dehydrogenase increased, laryngismus, leukocytosis, leukopenia, libido increased, loss of balance, lymphadenopathy, maculopapular rash, manic reaction, melena, MI, migraine, moniliasis, myasthenia, myoclonus, neoplasia, neurosis, osteoporosis, otitis external, palpitation, paranoid reaction, parasitic infection, parosmia, pelvic pain, periodontal abscess, peripheral vascular disorder, pneumonia, polyuria (female), prostatic hyperplasia, rectal hemorrhage, salivation increased, skin hypertrophy, skin benign neoplasm, suicide attempt, syncope, tachycardia, tenosynovitis, tongue edema, twitching, urinary retention, urinary urgency (male and female), urination impaired (male), urticaria, vaginal hemorrhage, vaginal moniliasis, vaginitis, vasodilatation, vertigo, vesiculobullous rash, viral infection, visual field defect

ALERT: U.S. Boxed Warning

Suicidal thoughts and behaviors (transdermal patch):

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older.

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.

Selegiline transdermal patch is contraindicated in patients less than 12 years of age because of an increased risk of hypertensive crisis.

Warnings/Precautions

Major psychiatric warnings (transdermal patch):

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increased risk in patients >24 years of age; there was a trend toward reduced risk in patients ≥65 years. Closely monitor patients of all ages who are started on antidepressant therapy for clinical worsening, and emergence of suicidal thoughts and behaviors, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Transdermal selegiline is contraindicated for use in children <12 years of age.

• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.

Concerns related to adverse effects:

• Blood pressure effects: Oral formulations: May cause exacerbation of hypertension. May also cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia). Incidence of orthostatic hypotension may also be increased in older adults and when titrating the dose. Monitor patients for new onset or exacerbation of hypotension, new onset hypertension or hypertension not adequately controlled after starting selegiline.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). Somnolence and falling asleep while engaged in activities of daily living (including operation of motor vehicles) have been reported with the orally disintegrating tablet; some cases reported that there were no warning signs for the onset of symptoms. Symptom onset may occur well after initiation of treatment; some events have occurred >1 year after initiation of treatment. Prior to treatment initiation, evaluate for factors that may increase these risks such as concomitant sedating medications and the presence of sleep disorders. Monitor for drowsiness or sleepiness. If significant daytime sleepiness or episodes of falling asleep during activities that require active participation occur (eg, driving, conversations, eating), discontinue selegiline. There is insufficient information to suggest that dose reductions will eliminate these symptoms. If therapy is continued, advise patient to avoid driving and other potentially dangerous activities.

• Dyskinesia: Oral formulations: May potentiate the dopaminergic side effects of levodopa and cause dyskinesia or exacerbate preexisting dyskinesia requiring a reduction of the dose of levodopa.

• Impulse control disorders: Dopaminergic agents used for Parkinson disease have been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), uncontrolled spending of money, binge eating, and/or other intense urges. Causality has not been established, and controversy exists as to whether this phenomenon is related to the underlying disease, prior behaviors/addictions and/or drug therapy. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases.

• Melanoma: Risk for melanoma development is increased in Parkinson disease patients; drug causation or factors contributing to risk have not been established. Patients should be monitored closely and periodic skin examinations should be performed.

• Psychosis: Orally disintegrating tablets: May cause new or worsening mental status and behavioral changes (may be severe) including hallucinations and psychotic-like behavior with initiation of therapy, after dose increases, or during the course of therapy. Symptoms may consist of paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Avoid use in patients with a major psychotic disorder.

• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with concomitant use of serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.

Disease-related concerns:

• Hepatic impairment: Use oral products with caution in patients with hepatic impairment; dosage adjustments may be necessary with orally disintegrating tablets in patients with mild to moderate hepatic impairment (Child-Pugh class A and B); orally disintegrating tablets are not recommended in patients with severe hepatic impairment (Child-Pugh class C).

• Mania/hypomania: Transdermal patch: May precipitate a shift to mania or hypomania in patients at risk for bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder, including a family history of suicide, bipolar disorder, and depression. Selegiline is not FDA approved for the treatment of bipolar depression.

• Renal impairment: Use oral products with caution in patients with renal impairment; orally disintegrating tablets are not recommended in patients with severe renal impairment (CrCl <30 mL/minute) and ESRD.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Surgical patients: According to many of MOA inhibitor manufacturers, use within 10 days prior to elective surgery is contraindicated. The decision to continue or withhold MAO inhibitors must be done in collaboration with the patient's psychiatrist. Currently, an MAO-safe anesthetic technique which excludes the use of meperidine and indirect-acting adrenergic agonists is recommended for patients requiring continued MAO inhibitor therapy (Huyse 2006).

Dosage form specific issues:

• Orally disintegrating tablet: May cause irritation of buccal mucosa including swallowing pain, mouth pain, discrete areas of focal reddening, multiple foci of reddening, edema, and/or ulceration.

• Phenylalanine: Orally disintegrating tablet: May contain phenylalanine; use caution in patients with phenylketonuria.

• Transdermal patch: Avoid exposure of application site and surrounding area to direct external heat sources (eg, heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight); may increase drug absorption.

Other warnings/precautions:

• Antidepressant discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. More severe symptoms have also been associated with MAO inhibitors. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).

• Antiparkinsonian discontinuation syndrome: Abrupt discontinuation or interruption of antiparkinsonian therapy has been associated with a discontinuation syndrome, which may resemble neuroleptic malignant syndrome; symptoms may include elevated temperature, muscular rigidity, altered consciousness and autonomic instability.

• Tyramine-containing products: Nonselective MAO inhibition occurs with transdermal delivery and is necessary for antidepressant efficacy. Hypertensive crisis as a result of ingesting tyramine-rich foods is always a concern with nonselective MAO inhibition. Although transdermal delivery minimizes inhibition of MAO-A in the gut, there is limited data with higher transdermal doses; dietary modifications are recommended with doses ≥9 mg/24 hours. Discontinue therapy immediately if hypertensive crisis occurs. With the oral product, MAO-B selective inhibition should not pose a problem with tyramine-containing products as long as the typical oral doses are employed, however, rare hypertensive reactions have been reported. Increased risk of nonselective MAO inhibition occurs with oral capsule/tablet doses >10 mg/day or orally disintegrating tablet doses >2.5 mg/day.

Monitoring Parameters

Blood pressure; symptoms of parkinsonism; general mood and behavior (increased anxiety, presence of mania or agitation); suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased); periodic skin examinations; symptoms of serotonin syndrome (transdermal patch)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, nausea, vomiting, insomnia, diarrhea, back pain, rhinorrhea, or rhinitis. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, illogical thinking), signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), severe fatigue, falling asleep during activities, abnormal movements, twitching, change in balance, difficulty speaking, dysphagia, tremors, difficulty moving, rigidity, severe headache, severe dizziness, passing out, confusion, mood changes, behavioral changes, hallucinations, uncontrollable urges, skin growths, mole changes, angina, muscle pain, muscle weakness, neck rigidity, mouth sores, pain with swallowing, or severe skin irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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