VA Class:CN500

VA Class:CN602

AHFS Class:

• Monoamine Oxidase B Inhibitors 28:36.32

Generic Name(s):

• Rasagiline Mesylate

Chemical Name:

• ( R )-2,3-dihydro- N -2-propynyl-1 H -inden-1-amine methanesulfonate

Molecular Formula:

• C₁₂H₁₃N•CH₄O₃S

Rasagiline mesylate, a propargylamine, is a selective and irreversible inhibitor of monoamine oxidase-B (MAO-B).1,2,3,4,5,158

Parkinsonian Syndrome

Rasagiline is used for the symptomatic treatment of parkinsonian syndrome (e.g., parkinsonism, Parkinson disease [paralysis agitans]).1,2 Rasagiline may be used as monotherapy or as adjunctive therapy to levodopa (see Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16) or other antiparkinsonian agents (e.g., dopamine agonists).1

Efficacy of rasagiline as initial monotherapy in the management of parkinsonian syndrome has been established in a randomized, double-blind, placebo-controlled study of up to 26 weeks' duration in patients with early disease who were not receiving dopaminergic antiparkinsonian agents or had not received any antiparkinsonian drug therapy.1,2,5 In this study, 404 patients were randomized to receive rasagiline (1 or 2 mg once daily) or placebo; patients were not permitted to use levodopa, dopamine agonists, selegiline, or amantadine but could receive stable dosages of an anticholinergic agent as needed.1,5,8 The primary efficacy measurement was the change from baseline in the total score (i.e., combined scores from part I [mentation], part II [activities of daily living], and part III [motor function]) of the Unified Parkinson's Disease Rating Scale (UPDRS); a reduction in the total score represented an improvement in mentation, activities of daily living, and/or motor function.1,5 Treatment with rasagiline was associated with substantially smaller increases in the UPDRS score (i.e., less functional decline) compared with treatment with placebo; efficacy of rasagiline dosages of 1 or 2 mg daily was comparable.1,5,8

Efficacy of rasagiline as an adjunct to levodopa in the management of parkinsonian syndrome has been established in 2 multicenter, randomized, double-blind, placebo-controlled studies in patients with more advanced disease who were receiving long-term levodopa therapy (mean duration: 8 years; range: 5 months-32 years) in combination with a decarboxylase inhibitor and were experiencing motor fluctuations (e.g., end-of-dose “ wearing off”, sudden or random “off” phenomena).1,3,4 In the first study, 472 patients were randomized to receive rasagiline (0.5 or 1 mg daily) or placebo for 26 weeks;1,2,4 in the second study, 687 patients were randomized to receive rasagiline (1 mg daily), entacapone (200 mg with every levodopa dose), or placebo for 18 weeks.1,2,3 Patients in both studies continued receiving levodopa (average dosage: 700-800 mg daily) and were permitted to receive stable dosages of other antiparkinsonian agents; dopamine agonists were used in approximately 65% of patients in both studies, and entacapone was used in 35% of patients in the first study.1,3,4 The primary efficacy measurement was the change from baseline in the mean number of total daily hours spent in the “off” state (period of poor functioning and mobility), as measured by 24-hour home diaries.1,2,3,4,8 In these studies, therapy with rasagiline (1 mg daily) or entacapone was more effective than placebo in decreasing total daily “off” time;1,3,8 therapy with a lower dosage of rasagiline (0.5 mg daily) also resulted in decreased “off” time, but to a lesser extent.1,4 Duration of “off” time was reduced by a mean of 1.2-1.9, 1.4, 1.2, or 0.4-0.9 hours in patients receiving rasagiline 1 mg, rasagiline 0.5 mg, entacapone, or placebo, respectively.1,3,4 In addition, compared with placebo, treatment with rasagiline or entacapone was associated with substantial improvements in the UPDRS activities of daily living (ADL) score during the “off” period and the UPDRS motor function score during the “on” period.1,3,4 During the first 6 weeks of therapy, reduction in levodopa dosage was permitted if adverse dopaminergic effects (e.g., dyskinesia, hallucinations) occurred or worsened.1,3,4 In these studies, levodopa dosage was reduced in 9-17 or 6-8% of patients receiving rasagiline or placebo, respectively; levodopa dosage was reduced on average by about 9-13% in patients receiving rasagiline or about 7-13% in those receiving placebo.1

Efficacy of rasagiline as adjunctive therapy to other antiparkinsonian agents has been established in a multicenter, randomized, double-blind, placebo-controlled study in patients with parkinsonian syndrome (average disease duration of 2 years) who were receiving stable dosages of a dopamine agonist (ropinirole or pramipexole) for at least 30 days but were continuing to experience symptoms.1 Patients were randomized to receive adjunctive therapy with rasagiline 1 mg daily or placebo for 18 weeks.1 Compared with placebo, therapy with rasagiline resulted in greater improvements in the total UPDRS score, which was largely attributed to improvements in the motor function component of the score.1

Administration

Rasagiline mesylate is administered orally once daily without regard to meals.1,2

Dosage

The recommended adult dosage of rasagiline as monotherapy or as adjunctive therapy with other antiparkinsonian agents (other than levodopa) in the management of parkinsonian syndrome is 1 mg once daily.1

The recommended initial adult dosage of rasagiline as adjunctive therapy with levodopa for the management of parkinsonian syndrome is 0.5 mg once daily.1 If an adequate response is not achieved, dosage may be increased to 1 mg once daily as tolerated.1

The recommended dosages of rasagiline should not be exceeded because of the risk of serious hypertensive reactions.1

During adjunctive therapy with levodopa, reduction in levodopa dosage may be considered if adverse dopaminergic effects (e.g., dyskinesia, hallucinations) occur.1 In clinical studies, approximately 9-17% of patients receiving 0.5 or 1 mg of rasagiline daily required a reduction in levodopa dosa the average reduction in the daily levodopa dosage was about 9-13%.1 (See Uses: Parkinsonian Syndrome.)

Concomitant use of rasagiline with ciprofloxacin or other cytochrome P-450 (CYP) isoenzyme 1A2 inhibitors may increase plasma rasagiline concentrations by up to twofold.1 When used concomitantly with ciprofloxacin or other CYP1A2 inhibitors,1,2,8 rasagiline dosage should not exceed 0.5 mg once daily.1

Special Populations

In patients with mild (Child-Pugh score of 5-6) hepatic impairment, dosage of rasagiline should not exceed 0.5 mg once daily; rasagiline should not be used in patients with moderate or severe (Child-Pugh score of 7 or greater) hepatic impairment.1,2 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment is necessary in patients with mild or moderate renal impairment or in geriatric patients.1

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 monoamine oxidase (MAO) inhibitors (selective or nonselective).1 (See Drug Interactions.)

Warnings/Precautions

Hypertension

Rasagiline may cause hypertension or exacerbate existing hypertension.1 Substantial increases in blood pressure (systolic blood pressure exceeding 180 mm Hg or diastolic blood pressure exceeding 100 mm Hg) have been reported in 4% of patients receiving rasagiline 1 mg daily as adjunctive therapy with levodopa compared with 3% of patients receiving placebo.1 Posttreatment hypertension (systolic blood pressure exceeding 180 mm Hg or diastolic blood pressure exceeding 100 mm Hg) combined with substantial increases in blood pressure from baseline (increases in systolic or diastolic blood pressure of greater than 30 or 20 mm Hg, respectively) occurred in more patients who received rasagiline 1 mg daily (2%) than in those who received placebo (1%).1

Patients receiving rasagiline should be monitored for new-onset hypertension or hypertension that is not adequately controlled.1 Dosage adjustment of antihypertensive drugs may be necessary if elevation of blood pressure is sustained.1

Serious hypertensive reactions associated with nonselective inhibition of MAO may occur with use of higher than recommended dosages of selective MAO-B inhibitors.1 At rasagiline dosages exceeding 0.5 or 1 mg daily, relative selectivity for MAO-B diminishes and the likelihood of hypertensive reactions increases.1 To minimize this risk, patients should not exceed recommended dosages of rasagiline.1 (See Dosage and Administration: Dosage.) Concomitant use of rasagiline with other MAO inhibitors also may increase the risk of nonselective MAO inhibition and cause hypertensive crisis.1

Severe hypertensive reactions including hypertensive crisis have been reported rarely following concomitant use of recommended dosages of selective MAO-B inhibitors with foods containing large amounts of tyramine or drug preparations containing sympathomimetic amines.1 Concomitant use of rasagiline with preparations containing sympathomimetic amines should be employed with caution.1 (See Drug Interactions: Sympathomimetic Amines.) The manufacturer states that restriction of tyramine-containing foods generally is not required during rasagiline therapy.1 However, because foods that contain very large amounts (i.e., more than 150 mg) of tyramine (e.g., aged cheeses) potentially can cause a hypertensive crisis in some patients (e.g., those with mildly increased sensitivity to tyramine) receiving recommended dosages of rasagiline, patients should be advised to avoid such tyramine-rich foods during rasagiline therapy.1 (For additional information on foods and beverages with high tyramine content, see Drug Interactions: Food and Drugs Associated with Hypertensive Crisis, in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.) Patients also should be instructed on how to recognize manifestations of a hypertensive crisis and to immediately notify a clinician if such manifestations occur.1 (See Advice to Patients.)

Serotonin Syndrome

Concomitant use of selective (e.g., rasagiline, selegiline) or nonselective (e.g., phenelzine, tranylcypromine) MAO inhibitors with antidepressants (e.g., selective serotonin-reuptake inhibitors [SSRIs], selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], tricyclic or tetracyclic antidepressants, triazolopyridine-derivative antidepressants) or certain opiate agonists (i.e., meperidine, tramadol) has resulted in severe serotonin syndrome, which potentially may be fatal.1 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,10

Because of the potential risk of severe, sometimes fatal, serotonin syndrome, concomitant use of rasagiline with certain opiate agonists (i.e., meperidine, methadone, propoxyphene [no longer commercially available in the US], tramadol) is contraindicated .1 (See Cautions: Contraindications and also see Drug Interactions: Opiate Agonists.) Although concomitant use of rasagiline with certain antidepressants was permitted during clinical trials, experience is insufficient to rule out the possibility of adverse effects from such concomitant use (see Drug Interactions: Antidepressant Agents).1

Sudden Sleep Episodes

Patients receiving dopaminergic agents have reported falling asleep while engaged in activities of daily living, including operating a motor vehicle (which has sometimes resulted in accidents).1 Although many patients reported somnolence while receiving rasagiline, some patients did not perceive warning signs, such as excessive drowsiness, and believed they were alert prior to the episode of falling asleep.1 Some of the cases were reported as late as 1 year after initiation of therapy.1 It is thought that falling asleep while engaged in such activities always occurs in a setting of preexisting somnolence, although patients may not give such a history.1 Patients may not acknowledge drowsiness or sleepiness until directly questioned about these adverse effects during specific activities.1

Prior to initiating rasagiline therapy, patients should be advised of the potential to develop drowsiness and specifically asked about any factors that may increase the risk of somnolence (e.g., concomitant use of sedating drugs, presence of sleep disorders).1 Patients should be continually reassessed for drowsiness or sleepiness during therapy, especially since some of the episodes of falling asleep occur well after starting treatment.1 If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), rasagiline generally should be discontinued.1 If a decision is made to continue therapy, the patient should be advised not to drive and to avoid other potentially dangerous activities.1 There is insufficient information to establish whether dosage reduction will eliminate episodes of falling asleep while engaged in activities of daily living.1 (See Advice to Patients.)

Concomitant Use with Ciprofloxacin or Other CYP1A2 Inhibitors

Concomitant use of rasagiline with ciprofloxacin or other cytochrome P-450 (CYP) isoenzyme 1A2 inhibitors may increase plasma rasagiline concentrations by up to twofold.1 Adjustment of rasagiline dosage is recommended.1,8 (See Dosage and Administration: Dosage and also see Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Orthostatic Hypotension and Lowering of Blood Pressure

Orthostatic hypotension, with or without manifestations such as dizziness, nausea, syncope, and sometimes sweating, has been reported in patients receiving rasagiline as adjunctive therapy with levodopa.1 In clinical studies in patients receiving adjunctive therapy with rasagiline and levodopa, orthostatic hypotension was reported in 6 or 9% of patients receiving rasagiline 0.5 or 1 mg daily, respectively, and resulted in discontinuance of the drug in 0 or 0.7% of these patients, respectively.1 Orthostatic hypotension consisting of decreases in systolic and diastolic blood pressure of at least 30/20 mm Hg was reported in 13% of patients receiving rasagiline 1 mg daily as adjunctive therapy with levodopa, compared with 9% of those receiving placebo.1 In a clinical study evaluating adjunctive therapy with rasagiline and a dopamine agonist, orthostatic hypotension was reported in 3.1% of patients receiving rasagiline compared with 0.6% of those receiving placebo.1 Data from clinical studies indicate that orthostatic hypotension occurs most frequently during the first 2 months of rasagiline therapy (and less frequently over time) and may occur at any time following an increase in dosage.1 Substantial decreases in blood pressure in the supine position also have been reported in some patients receiving rasagiline.1 Posttreatment hypotension (systolic blood pressure less than 90 mm Hg or diastolic blood pressure less than 50 mm Hg) combined with substantial decreases in blood pressure from baseline (decreases in systolic or diastolic blood pressure of greater than 30 or 20 mm Hg, respectively) occurred in more patients receiving rasagiline 1 mg daily (3.2%) compared with those receiving placebo (1.3%).1

The risk of hypotension or orthostatic hypotension does not appear to be increased when rasagiline (1 mg daily) is used as monotherapy.1

Dyskinesia

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

Hallucinations and Psychotic-like Behavior

Hallucinations were reported in approximately 1.3% of patients receiving rasagiline 1 mg daily as monotherapy and resulted in discontinuance of the drug in 1.3% of patients.1 When rasagiline was used as adjunctive therapy with levodopa, hallucinations occurred in 4-5% of patients receiving rasagiline 0.5 or 1 mg daily and resulted in discontinuance of the drug in 1% of patients.1 In a study evaluating adjunctive therapy with rasagiline and a dopamine agonist, hallucinations occurred in 1.2 or 1.8% of patients receiving rasagiline or placebo, respectively.1 Patients should be cautioned about the possibility of developing hallucinations and instructed to notify a clinician promptly should these manifestations occur.1

New onset or exacerbation of psychotic-like behavior (manifested as paranoia, confusional state or confusion, psychotic disorder, agitation, delusion, and hallucinations) has been reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone, including rasagiline.1 Therefore, rasagiline should not be used in patients with a major psychotic disorder.1 Furthermore, concomitant use of rasagiline with antipsychotic agents that decrease central dopaminergic tone may result in decreased effectiveness of rasagiline.1

If a patient develops hallucinations or psychotic-like behaviors while receiving rasagiline, consideration should be given to reducing the dosage or discontinuing the drug.1

Intense Urges

Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges have been reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including rasagiline).1 These urges stopped in some cases when dosage was reduced or the drug was discontinued.1 Clinicians should ask patients whether they have developed new or increased gambling urges, sexual urges, or other urges while receiving rasagiline.1 If a patient develops such urges while receiving rasagiline, consideration should be given to reducing the dosage or discontinuing the drug.1

Neuroleptic Malignant Syndrome

A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability) has been reported in association with rapid dosage reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.1

Melanoma

Data from epidemiologic studies indicate that patients with Parkinson disease have a twofold to approximately sixfold greater risk of developing melanoma than the general population; however, it is unclear whether the observed increased risk is related to Parkinson disease or other factors (e.g., drugs used to treat the disease).1

Because of these findings, patients should be monitored for melanoma on a frequent and regular basis.1 The manufacturer recommends that dermatologic examinations be performed by qualified clinicians (e.g., dermatologists) periodically;1 the frequency of dermatologic examinations should be determined by the patient's dermatologist.8

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

Lactation

Rasagiline inhibits prolactin secretion in rats; the drug may inhibit milk secretion in women.1,8 It is not known whether rasagiline is distributed into milk; caution is advised if the drug is administered in nursing women.1

Pediatric Use

Safety and efficacy of rasagiline have not been established in pediatric patients younger than 18 years of age.1,8

Geriatric Use

Approximately half of patients in clinical studies were 65 years of age or older.1 No overall differences in safety relative to younger adults were observed.1

Hepatic Impairment

Following administration of rasagiline 1 mg daily for 7 days, the area under the plasma concentration-time curve (AUC) or peak plasma concentration of rasagiline was increased by twofold or 1.4-fold, respectively, in individuals with mild (Child-Pugh score of 5-6) hepatic impairment and by sevenfold or twofold, respectively, in individuals with moderate (Child-Pugh score of 7-9) hepatic impairment.1

Dosage adjustment is recommended in patients with mild hepatic impairment.1 (See Dosage and Administration: Special Populations.) Use is not recommended in patients with moderate or severe (Child-Pugh score of 7 or greater) hepatic impairment.1,2

Renal Impairment

Following administration of rasagiline 1 mg daily for 8 days, AUC of rasagiline was similar between individuals with moderate renal impairment and those with normal renal function, while AUC of the major metabolite 1-aminoindan increased by 1.5-fold in individuals with moderate renal impairment.1 Because 1-aminoindan is not an MAO inhibitor, no dosage adjustment is needed in patients with mild or moderate renal impairment.1 Data are not available for patients with severe renal impairment.1

Common Adverse Effects

When rasagiline is used as initial monotherapy, the most common adverse effects (i.e., occurring at least 3% more frequently in patients receiving rasagiline than in those receiving placebo) include flu syndrome,1 arthralgia,1,5 depression,1 and dyspepsia.1 Other adverse effects reported in 2% or more of patients receiving rasagiline as initial monotherapy and occurring more frequently with rasagiline than with placebo include fall,1 headache,1,5 conjunctivitis,1 fever,1 gastroenteritis,1 rhinitis,1 arthritis,1 ecchymosis,1 malaise,1 neck pain,1 paresthesia,1 and vertigo.1,8

When rasagiline is used as adjunctive therapy with levodopa, the most common adverse effects (i.e., occurring at least 3% more frequently in patients receiving rasagiline than in those receiving placebo) include 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 and fall.1 Other adverse effects reported in 2% or more of patients receiving rasagiline as initial monotherapy and occurring more frequently with rasagiline than with placebo include ecchymosis,1 somnolence,1,3 paresthesia,1 headache, 1 diarrhea,1,3 dyspepsia,1 hallucinations,1,3 ataxia,1 dyspnea,1 infection,1 neck pain,1 sweating,1 tenosynovitis,1 dystonia,1 gingivitis,1 hemorrhage,1 hernia, and myasthenia.1,8

When rasagiline is used as adjunctive therapy with a dopamine agonist, the most common adverse effects include peripheral edema, fall, arthralgia, cough, and insomnia.1

Rasagiline is extensively metabolized, mainly via hepatic cytochrome P-450 (CYP) 1A2 isoenzyme.1,2 The drug does not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4, or 4A in vitro.1,2

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP1A2: Pharmacokinetic interaction observed during concomitant use with ciprofloxacin (increased plasma rasagiline concentrations).1,2 Dosage of rasagiline should be limited to 0.5 mg once daily in patients receiving the drug concomitantly with ciprofloxacin or other CYP1A2 inhibitors.1,8

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2: Pharmacokinetic interaction with theophylline or other substrates of CYP1A2 unlikely.1,2

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

Antidepressant Agents

Potential pharmacologic interaction resembling serotonin syndrome.1 (See Serotonin Syndrome under Cautions: Warnings/Precautions.) At least 14 days should elapse between discontinuance of rasagiline and initiation of a selective serotonin-reuptake inhibitor (SSRI), selective serotonin- and norepinephrine-reuptake inhibitor (SNRI), tricyclic or tetracyclic antidepressant, or triazolopyridine-derivative antidepressant.1 Because both fluoxetine and its principal metabolite have relatively long half-lives, the manufacturer of rasagiline recommends that at least 5 weeks (or longer with high-dose or long-term fluoxetine therapy) elapse between discontinuance of fluoxetine therapy and initiation of rasagiline.1

Cyclobenzaprine

Concomitant use is contraindicated.1

Dextromethorphan

Potential pharmacologic interaction (brief episodes of psychosis or bizarre behavior).1 Concomitant use is contraindicated.1

Dopamine Antagonists

Concomitant use of rasagiline and dopamine antagonists (e.g., metoclopramide) or antipsychotic agents that decrease central dopaminergic tone may result in decreased efficacy of rasagiline.1

Levodopa

Potential pharmacologic (increased adverse dopaminergic effects, increased risk of dyskinesia and orthostatic hypotension) and pharmacokinetic interaction (modest increase in plasma rasagiline concentrations).1,2 Reduction in levodopa dosage may be considered; adjustment of rasagiline dosage is not necessary.1 (See Dosage and Administration: Dosage.)

Monoamine Oxidase Inhibitors

Potential pharmacokinetic interaction (increased risk of nonselective monoamine oxidase [MAO] inhibition, possibly resulting in a hypertensive crisis).1 Concomitant use of rasagiline with nonselective or selective inhibitors of MAO is contraindicated.1 At least 14 days should elapse between discontinuance of rasagiline and initiation of other MAO inhibitors.1

Opiate Agonists

Pharmacologic interaction resembling serotonin syndrome has been reported following concomitant use of MAO inhibitors, including selective MAO-B inhibitors, with meperidine.1,2 Serotonin syndrome has been reported in at least one patient receiving higher than recommended dosage of rasagiline (4 mg daily) concomitantly with tramadol.1 (See Serotonin Syndrome under Cautions: Warnings/Precautions.) Therefore, concomitant use of rasagiline with meperidine, methadone, propoxyphene (no longer commercially available in the US), or tramadol is contraindicated.1,2 At least 14 days should elapse between discontinuance of rasagiline and initiation of these opiate agonists.1

St. John's wort ( Hypericum perforatum )

Concomitant use is contraindicated.1

Sympathomimetic Amines

Severe hypertension or hypertensive crisis may occur following concomitant use of rasagiline with sympathomimetic drugs.1 Severe hypertension has been reported in patients receiving rasagiline with ophthalmic solutions containing sympathomimetic amines.1 Therefore, caution is advised when rasagiline is used concomitantly with preparations (including oral, nasal, and ophthalmic preparations) containing sympathomimetic amines (e.g., amphetamines, ephedrine, phenylephrine, pseudoephedrine).1

Tyramine-rich Foods or Beverages

Concomitant use of rasagiline with tyramine-rich foods or beverages may result in substantially elevated blood pressure or hypertensive crisis.1 (See Hypertension under Cautions: Warnings/Precautions and also see Description.) The manufacturer states that while it generally is not necessary to restrict ingestion of most foods or beverages that may contain tyramine, ingestion of certain foods containing very large amounts (i.e., more than 150 mg) of tyramine (e.g., aged cheeses such as Stilton cheese) potentially may result in a hypertensive crisis and, thus, should be avoided during rasagiline therapy.1

Description

Rasagiline mesylate, a propargylamine, is an irreversible monoamine oxidase-B (MAO-B) inhibitor.1,2,3,4,5 MAO is a mitochondrial enzyme that regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues.1 There appear to be at least 2 isoforms of MAO, MAO-A and MAO-B, which differ in localization and substrate specificity.2 MAO-A, predominantly found in the GI tract and liver, regulates the metabolic degradation of circulating catecholamines and dietary amines (e.g., tyramine).1,2 MAO-B, predominantly found in the brain, regulates the metabolic degradation of dopamine and phenylethylamine.1,2 Inhibition of MAO-A in the periphery results in systemic absorption of dietary amines (e.g., tyramine), which, in substantial amounts, can cause release of norepinephrine and subsequent substantial increases in blood pressure.1,2 (See Hypertension under Cautions: Warnings/Precautions.) Inhibition of MAO-B results in increased extracellular concentrations of dopamine and, therefore, enhanced dopaminergic activity in the striatum.1,2,3 While the precise mechanisms of activity of rasagiline have not been fully characterized, data from ex vivo animal studies indicate that the drug potently and irreversibly inhibits MAO-B in brain, liver, and intestinal tissues;1,6 the selectivity of rasagiline in inhibiting MAO-B (and not MAO-A) is dose related and diminishes as dosage of the drug is increased above the recommended daily dosage.1

Rasagiline is rapidly absorbed; following oral administration, peak plasma concentrations are achieved in approximately 1 hour.1,2 The absolute bioavailability of rasagiline is about 36%.1,2 Following administration with a high-fat meal, peak plasma rasagiline concentrations and area under the plasma concentration-time curve (AUC) decreased by approximately 60 and 20%, respectively; because AUC is not substantially affected, rasagiline may be administered with or without food.1,2 Rasagiline readily crosses the blood-brain barrier.2,8 The mean steady-state or terminal half-life of rasagiline is 31 or 1.342 hours, respectively; however, there is no correlation between rasagiline's pharmacokinetic profile and its pharmacologic effects because the drug irreversibly inhibits MAO-B, and restoration of normal enzyme activity depends on the rate of de novo enzyme synthesis.1,2 Rasagiline is approximately 88-94% bound to plasma proteins, with 61-63% bound to albumin.1

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion.1 The drug is metabolized via dealkylation and/or hydroxylation by the cytochrome P-450 (CYP) microsomal enzyme system, principally by isoenzyme 1A2.1,2 Approximately 62 and 7% of an oral dose of rasagiline is excreted in urine and feces, respectively, as metabolites over 7 days; less than 1% of the drug is excreted as unchanged drug in urine.1,2

Advice to Patients

Risk of hypertension and hypertensive crisis; importance of not exceeding the maximum recommended daily dosage of rasagiline and of avoiding foods containing very large amounts of tyramine (e.g., aged cheeses).1 Importance of advising patients to contact their clinician if they experience an increase in blood pressure.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 rasagiline as prescribed.1 If a dose is missed, omit the dose and administer the 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.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Teva Neuroscience, Inc. Azilect^® (rasagiline mesylate) tablets prescribing information. Overland Park, KS; 2014 May. [Web]

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. [PubMed 16027398]

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. [PubMed 15766996]

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. [PubMed 15710852]

5. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: The TEMPO Study. Arch Neurol . 2002; 59:1937-43. [PubMed 12470183]

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. [PubMedCentral][PubMed 11159700]

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. [PubMed 18041937]