Generic Name: 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

Introduction

Irreversible MAO-B inhibitor.^{1 2 3 4 5}

Uses for Azilect

Parkinsonian Syndrome

Symptomatic treatment of idiopathic parkinsonian syndrome.^{1 2}

Used as initial monotherapy in patients with early disease^{1 2 5} or as adjunctive therapy to levodopa in patients with more advanced disease who exhibit a deteriorating response to levodopa/carbidopa.^{1 2 3 4}

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Azilect Dosage and Administration

General

Concomitant Levodopa/Carbidopa Therapy

• Consider reduction of 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

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

Oral

1 mg once daily.¹

Adjunctive Therapy with Levodopa

Oral

Initially, 0.5 mg once daily.¹

If adequate response is not achieved, may increase dosage to 1 mg once daily.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 Azilect

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.¹ (See Interactions.)

Warnings/Precautions

Concomitant Use with Antidepressants or Certain Opiate Agonists

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.)

Concomitant Use with Ciprofloxacin or Other CYP1A2 Inhibitors

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

Hypertensive Crisis

Hypertensive crisis (i.e., cheese reaction) reported rarely following concomitant use of recommended dosages of a selective MAO inhibitor (including rasagiline) with tyramine-rich foods or sympathomimetic amines (e.g., ephedrine).¹ (See Interactions and see also Advice to Patients.)

Risk of hypertensive reactions increases at dosages exceeding recommended daily dosage (selectivity of rasagiline for MAO-B diminishes as dosage increases).¹ Do not exceed recommended dosage of 1 mg daily (or 0.5 mg daily in patients with mild hepatic impairment or in patients receiving concomitant ciprofloxacin or other CYP1A2 inhibitors).¹

Melanoma

Epidemiologic studies indicate patients with Parkinson’s disease have a twofold to approximately sixfold greater risk of developing melanoma than the general population.¹ Unclear whether increased risk is related to Parkinson's 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

Exacerbation of Levodopa-associated Adverse Effects

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

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

Elevation of BP

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

Risk of hypertension not increased when used as monotherapy.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 a major psychotic disorder.¹ (See Specific Drugs and Foods under Interactions.)

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

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 Although causal relationship not established, 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

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

Interactions for Azilect

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

Consider the possibility of interactions such as those reported with nonselective MAO inhibitors.¹

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 2A6, 2C9, 2C19, 2D6, 2E1, 3A4, or 4A: Pharmacokinetic interaction unlikely.^{1 2}

Specific Drugs and Foods

Drug	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	Reduction of levodopa dosage may be considered; adjustment of rasagiline dosage not necessary1 Combination used to therapeutic advantage1
MAO inhibitors (e.g., phenelzine, tranylcypromine)	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
Opiate agonists (e.g., meperidine, methadone, propoxyphene [no longer commercially available in US], tramadol)	Potential for serious, possibly fatal adverse effects resembling 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 meperidine1
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 amphetamines, ephedrine, phenylephrine, or pseudoephedrine1 8
Theophylline	Pharmacokinetic interaction unlikely1 2

Azilect 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) by1.5-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 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, such as Stilton cheese).¹ (See Hypertensive Crisis under Cautions.) Importance of recognizing manifestations of a hypertensive crisis (e.g., severe headache, blurred vision or visual disturbances, difficulty thinking, stupor or coma, seizures, chest pain, unexplained nausea or vomiting, manifestations of a stroke⁹ ) and contacting a clinician if these or other new or unusual manifestations occur.¹

• Importance of monitoring for melanoma frequently and receiving dermatologic examinations (i.e., performed by dermatologists) periodically.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 or following an increase in dosage.¹

• Risk of increased BP or exacerbation of hypertension.¹ Importance of informing patients that dosage adjustments may be necessary.¹

• Risk of hallucinations or psychotic-like behavior.¹ Importance of informing clinicians promptly if hallucinations occur.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.

Rasagiline Mesylate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	0.5 mg (of rasagiline)	Azilect	Teva Neuroscience
		1 mg (of rasagiline)	Azilect	Teva Neuroscience

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Azilect 0.5MG Tablets (TEVA NEUROSCIENCE): 30/$420.00 or 90/$1,156.95

Azilect 1MG Tablets (TEVA NEUROSCIENCE): 30/$407.01 or 90/$1,154.92