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Rasagiline Mesylate

Class: Monoamine Oxidase B Inhibitors
VA Class: CN500
Chemical Name: (R)-2,3-dihydro-N-2-propynyl-1H-inden-1-amine methanesulfonate
Molecular Formula: C12H13N•CH4O3S
CAS Number: 161735-79-1
Brands: Azilect

Medically reviewed on May 7, 2018

Introduction

See also: Gocovri

Selective irreversible MAO-B inhibitor.1 2 3 4 5 158

Uses for Rasagiline Mesylate

Parkinsonian Syndrome

Symptomatic treatment of parkinsonian syndrome (e.g., parkinsonism, Parkinson disease [paralysis agitans]).1 2

May be used as monotherapy1 2 5 or as adjunctive therapy to levodopa or other antiparkinsonian agents (e.g., dopamine agonists).1 2 3 4

Rasagiline Mesylate Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to meals.1 2

Dosage

Available as rasagiline mesylate; dosage expressed in terms of rasagiline.1

Adults

Parkinsonian Syndrome
Monotherapy or Adjunctive Therapy with Other Antiparkinsonian Agents (Other than Levodopa)
Oral

1 mg once daily.1

Adjunctive Therapy with Levodopa
Oral

Initially, 0.5 mg once daily.1

If adequate response not achieved, may increase dosage to 1 mg once daily as tolerated.1

Consider reducing levodopa dosage if adverse dopaminergic effects (e.g., dyskinesia, hallucinations) occur.1 In clinical studies, approximately 9–17% of patients receiving 0.5 or 1 mg rasagiline daily required reduction of levodopa dosage (average reduction: about 9–13%).1

Special Populations

Hepatic Impairment

0.5 mg once daily in patients with mild (Child-Pugh score of 5–6) hepatic impairment.1 2

Use not recommended in patients with moderate or severe (Child-Pugh score ≥7) hepatic impairment.1 2 (See Special Populations under Pharmacokinetics.)

Renal Impairment

No dosage adjustment required in patients with mild or moderate renal impairment.1

Geriatric Patients

No dosage adjustment required.1

Cautions for Rasagiline Mesylate

Contraindications

  • Concomitant use with cyclobenzaprine, dextromethorphan, meperidine, methadone, propoxyphene (no longer commercially available in the US), tramadol, St. John’s wort (Hypericum perforatum), or other MAO inhibitors (selective or nonselective).1 (See Interactions.)

Warnings/Precautions

Hypertension

Substantial increases in BP and posttreatment hypertension (SBP >180 mm Hg or DBP >100 mm Hg) reported in patients receiving rasagiline as adjunctive therapy with levodopa.1

Serious hypertensive reactions associated with nonselective inhibition of MAO may occur with use of higher than recommended dosages of rasagiline.1 Do not exceed recommended dosages.1 (See Dosage under Dosage and Administration.)

Hypertensive crisis reported rarely following concomitant use of recommended dosages of selective MAO-B inhibitors with tyramine-rich foods or sympathomimetic amines (e.g., ephedrine).1 Manufacturer states that restriction of most tyramine-containing foods generally not required during rasagiline therapy.1 However, because foods that contain very large amounts (i.e., >150 mg) of tyramine potentially can cause severe hypertension in some patients (e.g., those with mildly increased sensitivity to tyramine) receiving recommended dosages of rasagiline, advise patients to avoid such tyramine-rich foods during rasagiline therapy.1 (See Specific Drugs and Foods under Interactions and also see Advice to Patients.)

Serotonin Syndrome

Severe, potentially fatal reactions resembling serotonin syndrome reported following concomitant use of selective (e.g., rasagiline, selegiline) or nonselective (e.g., phenelzine, tranylcypromine) MAO inhibitors with antidepressants (e.g., SNRIs, SSRIs, tricyclic or tetracyclic antidepressants, triazolopyridine-derivative antidepressants) or certain opiate agonists (i.e., meperidine, tramadol).1 (See Interactions.)

Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, 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 10

Concomitant use with certain opiate agonists (i.e., meperidine, methadone, propoxyphene [no longer commercially available in the US], tramadol) is contraindicated.1 Concomitant use with antidepressants generally should be avoided.1 (See Specific Drugs and Foods under Interactions.)

Sudden Sleep Episodes

Episodes of falling asleep while engaged in activities of daily living (e.g., driving) reported, sometimes resulting in accidents.1

Some patients perceived no warning signs (e.g., excessive drowsiness) and believed that they were alert immediately prior to the event.1

Monitor patients for drowsiness or sleepiness.1 Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.1 Ask patients about any factors that may increase the risk of somnolence (e.g., concomitant sedating drugs, presence of sleep disorders).1

Generally discontinue therapy if a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating).1 If the drug is continued, advise patients not to drive and to avoid other potentially dangerous activities.1

Concomitant Use with Ciprofloxacin or Other CYP1A2 Inhibitors

Concomitant use with ciprofloxacin or other CYP1A2 inhibitors may increase plasma rasagiline concentrations by up to twofold.1 Adjustment of rasagiline dosage recommended.1 8 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Orthostatic Hypotension and Lowering of BP

Orthostatic hypotension, with or without manifestations such as dizziness, nausea, syncope, and sometimes sweating, reported when used as adjunctive therapy with levodopa.1 Occurs most frequently during the first 2 months of therapy (and less frequently over time) and may occur at any time following dosage increase.1 Substantial decreases in BP in the supine position and posttreatment hypotension also reported following use as adjunctive therapy.1

Risk of hypotension or orthostatic hypotension not increased when used as monotherapy.1

Dyskinesia

When used as adjunctive therapy with levodopa, rasagiline may precipitate or exacerbate levodopa-associated adverse effects (e.g., dyskinesia), presumably by increasing dopaminergic activity; effects may be mitigated by reducing levodopa dosage.1

Hallucinations and Psychotic-like Behavior

Hallucinations reported when used as monotherapy or as adjunctive therapy with levodopa.1 (See Advice to Patients.)

New onset or exacerbation of psychotic-like behavior (manifested as paranoia, confusional state or confusion, psychotic disorder, agitation, delusion, and hallucinations) reported.1 Use not recommended in patients with major psychotic disorders.1 (See Specific Drugs and Foods under Interactions.)

Consider reducing dosage or discontinuing rasagiline if a patient develops hallucinations or psychotic-like behavior.1

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 rasagiline).1 Urges stopped in some cases when dosage was reduced or drug was discontinued.1

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

Neuroleptic Malignant Syndrome

A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability) reported following rapid dosage reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.1 Hyperpyrexia not reported following discontinuance of rasagiline.1

Melanoma

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

Monitor for melanoma on a frequent and regular basis.1 Perform dermatologic examinations periodically;1 frequency of examinations determined by patient’s dermatologist.8

Specific Populations

Pregnancy

Category C.1

Lactation

Inhibits prolactin secretion in rats; may inhibit milk secretion in women.1 8 Not known whether rasagiline is distributed into milk; caution if used in nursing women.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1 8

Geriatric Use

No overall differences in safety relative to younger adults.1

Hepatic Impairment

Dosage adjustment recommended in patients with mild (Child-Pugh score of 5–6) hepatic impairment.1

Use not recommended in patients with moderate or severe (Child-Pugh score ≥7) hepatic impairment.1 2 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Monotherapy: Flu syndrome,1 arthralgia,1 5 depression,1 dyspepsia.1

Adjunctive therapy with levodopa: Dyskinesia,1 3 4 accidental injury,1 weight loss,1 4 orthostatic hypotension,1 3 vomiting,1 3 4 anorexia,1 4 arthralgia,1 abdominal pain,1 nausea,1 3 constipation,1 3 dry mouth,1 3 rash,1 abnormal dreams,1 3 fall.1

Adjunctive therapy with a dopamine agonist: Peripheral edema, fall, arthralgia, cough, insomnia.1

Interactions for Rasagiline Mesylate

Extensively metabolized, principally by CYP1A2; does not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4, or 4A in vitro.1 2

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP1A2 (e.g., ciprofloxacin): Possibly substantial (up to twofold) increase in plasma rasagiline concentrations.1 2 If used concomitantly, limit rasagiline dosage to 0.5 mg once daily.1 8

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2 (e.g., theophylline): Pharmacokinetic interaction unlikely.1 2

Substrates of CYP2A6, 2C9, 2C19, 2D6, 2E1, 3A4, or 4A: Pharmacokinetic interaction unlikely.1 2

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antidepressants (e.g., SNRIs, SSRIs, tetracyclics, tricyclics, triazolopyridine derivatives)

Potential for serious, possibly fatal adverse effects resembling serotonin syndrome1

Generally avoid concomitant use1

Allow ≥2 weeks to elapse between discontinuance of rasagiline and initiation of an SNRI, SSRI, tetracyclic, tricyclic, or triazolopyridine-derivative antidepressant1

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

Antipsychotics (i.e., those that decrease central dopaminergic tone)

Possible reduced effectiveness of rasagiline1

Ciprofloxacin

Substantial (83%) increase in AUC of rasagiline1

Limit rasagiline dosage to 0.5 mg once daily1

Cyclobenzaprine

Concomitant use contraindicated1

Dextromethorphan

Possible brief episodes of psychosis or bizarre behavior1

Concomitant use contraindicated1

Foods, tyramine-containing

Possible hypertensive crisis1

Avoid foods containing very large amounts of tyramine (e.g., aged cheeses, such as Stilton cheese)1 (see Advice to Patients)

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

Levodopa

Possible increased adverse dopaminergic effects and increased risk of dyskinesia and orthostatic hypotension1 2

Possible modest increase in plasma rasagiline concentrations1 2

May consider reduction of levodopa dosage1

Combination used to therapeutic advantage1

MAO inhibitors (selective or nonselective)

Possible increased risk of nonselective MAO inhibition, resulting in hypertensive crisis1

Concomitant use contraindicated1

Allow ≥2 weeks to elapse between discontinuance of rasagiline and initiation of other MAO inhibitors1

Metoclopramide

Possible reduced efficacy of rasagiline1

Opiate agonists (e.g., meperidine, methadone, propoxyphene [no longer commercially available in US], tramadol)

Potential for serious, possibly fatal serotonin syndrome1 2

Concomitant use with meperidine, methadone, propoxyphene, or tramadol is contraindicated1 2

Allow ≥2 weeks to elapse between discontinuance of rasagiline and initiation of these opiate agonists1

St. John's wort (Hypericum perforatum)

Concomitant use contraindicated1

Sympathomimetic amines (e.g., amphetamines, ephedrine, phenylephrine, pseudoephedrine)

Possible severe hypertensive reaction or hypertensive crisis1

Caution advised during concomitant use with sympathomimetic amines, including oral, nasal, and ophthalmic preparations1 8

Theophylline

Pharmacokinetic interaction unlikely1 2

Rasagiline Mesylate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak plasma concentration attained within approximately 1 hour.1 2

Absolute bioavailability is about 36%.1 2

Duration

Inhibition of platelet MAO-B in humans persists ≥1 week after last dose.1

Food

High-fat meals decrease peak plasma concentrations and AUC of rasagiline by approximately 60 and 20%, respectively.1 2 Because of modest effect on AUC, may administer rasagiline without regard to meals.1 2

Special Populations

Mild hepatic impairment (Child-Pugh score of 5–6) increases rasagiline AUC and peak plasma concentration by twofold and 1.4-fold, respectively; moderate hepatic impairment (Child-Pugh score of 7–9) increases rasagiline AUC and peak plasma concentration by sevenfold and twofold, respectively.1 (See Hepatic Impairment under Dosage and Administration.)

Moderate renal impairment increases AUC of 1-aminoindan (major metabolite of rasagiline) by 1.5-fold.1 Because 1-aminoindan does not inhibit MAO, no dosage adjustment needed in patients with mild or moderate renal impairment.1 Data not available for patients with severe renal impairment.1

Distribution

Extent

Readily crosses the blood-brain barrier.2 8

Plasma Protein Binding

Approximately 88–94% (with 61–63% bound to albumin).1

Elimination

Metabolism

Undergoes almost complete biotransformation in the liver prior to excretion.1 Metabolized via dealkylation and/or hydroxylation by CYP isoenzymes, principally CYP1A2.1 2

Elimination Route

Excreted in urine (62%) and feces (7%) as metabolites over 7 days; <1% excreted as unchanged drug in urine.1 2

Half-life

Mean steady-state or terminal half-life is 31 or 1.342 hours, respectively.1 2 However, no correlation between pharmacokinetic profile and pharmacologic effects because rasagiline irreversibly inhibits MAO-B, and restoration of normal enzyme activity depends on the rate of de novo enzyme synthesis.1 2

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15-30°C).1

Actions

  • Irreversible MAO-B inhibitor.1 2 3 4 5

  • Precise mechanism of activity not fully characterized, but data from ex vivo animal studies indicate rasagiline potently and irreversibly inhibits MAO-B in brain, liver, and intestinal tissues; also potently and irreversibly inhibits MAO-B in platelets.1 6 Selectivity in inhibiting MAO-B (and not MAO-A) is dose related and diminishes as dosage increases above recommended daily dosage.1

  • Inhibition of MAO-B results in increased extracellular concentrations of dopamine and, therefore, enhanced dopaminergic activity in the striatum.1 2 3

Advice to Patients

  • Risk of hypertension and hypertensive crisis; importance of not exceeding the maximum recommended daily dosage and of avoiding foods containing very large amounts of tyramine (e.g., aged cheeses).1 (See Hypertension under Cautions.) Importance of advising patients to contact their clinician if their BP increases.1

  • Importance of advising patients of the potential for sedating effects, including somnolence and the possibility of falling asleep without feeling drowsy or without warning while engaged in activities of daily living.1 Patients should avoid driving or engaging in other potentially dangerous activities until the effects on the individual are known.1

  • Importance of advising patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car) occur at any time during therapy, they should not drive or participate in potentially dangerous activities until they have contacted their clinician.1 Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of rasagiline.1 Patients should inform their clinician if they take any medications that make them drowsy before starting rasagiline therapy.1

  • Risk of new onset or exacerbation of dyskinesia when used concomitantly with levodopa.1

  • Risk of orthostatic hypotension, with or without manifestations such as dizziness, nausea, syncope, and sweating.1 Importance of advising patients to rise slowly after prolonged sitting or lying down, particularly during initial therapy.1

  • Risk of hallucinations or psychotic-like behavior.1 Importance of informing patients of the possible risk of exacerbating psychosis in those with major psychotic disorders.1

  • Importance of taking as prescribed.1 If a dose is missed, omit dose and administer next dose at the regularly scheduled time on the following day.1 Importance of advising patients to contact their clinician if they wish to discontinue therapy.1

  • Importance of asking patients whether they have developed any new or increased gambling urges, sexual urges, or other urges while receiving rasagiline and of advising them of the importance of reporting such urges.1

  • 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 (e.g., antidepressants, ciprofloxacin, opiate agonists) and OTC drugs (e.g., phenylephrine, pseudoephedrine), dietary supplements, and/or herbal products (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., hepatic impairment, major psychotic disorder).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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

Rasagiline Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.5 mg (of rasagiline)*

Azilect

Teva Neuroscience

Rasagiline Mesylate Tablets

1 mg (of rasagiline)*

Azilect

Teva Neuroscience

Rasagiline Mesylate Tablets

AHFS DI Essentials. © Copyright 2018, Selected Revisions May 7, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Teva Neuroscience, Inc. Azilect (rasagiline mesylate) tablets prescribing information. Overland Park, KS; 2014 May. From DailyMed website. http://dailymed.nlm.nih.gov

2. Chen JJ and Swope DM. Clinical pharmacology of rasagiline: A novel, second-generation propargylamine for the treatment of Parkinson disease. J Clin Pharmacol. 2005; 45:878-94. http://www.ncbi.nlm.nih.gov/pubmed/16027398?dopt=AbstractPlus

3. Rascol O, Brooks DJ, Melamed E et al for the LARGO study group. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): A randomised, double-blind, parallel-group trial. Lancet. 2005; 365:947-54. http://www.ncbi.nlm.nih.gov/pubmed/15766996?dopt=AbstractPlus

4. Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: The PRESTO Study. Arch Neurol. 2005; 62:241-8. http://www.ncbi.nlm.nih.gov/pubmed/15710852?dopt=AbstractPlus

5. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: The TEMPO Study. Arch Neurol. 2002; 59:1937-43. http://www.ncbi.nlm.nih.gov/pubmed/12470183?dopt=AbstractPlus

6. Youdim MBH, Gross A, and Finberg JPM. Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol. 2001; 132:500-6. http://www.ncbi.nlm.nih.gov/pubmed/11159700?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1572573&blobtype=pdf

8. Teva Neuroscience, Inc., Overland Park, KS: Personal communication.

10. Eli Lilly and Company. Cymbalta (duloxetine hydrochloride) delayed-release capsules prescribing information. Indianapolis, IN; 2011 Sep.

158. Fernandez HH, Chen JJ. Monoamine oxidase-B inhibition in the treatment of Parkinson's disease. Pharmacotherapy. 2007; 27:174S-185S. http://www.ncbi.nlm.nih.gov/pubmed/18041937?dopt=AbstractPlus

a. AHFS Drug Information. McEvoy GK, ed. Monoamine Oxidase Inhibitors General Statement. Bethesda, MD: American Society of Health-System Pharmacists.

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