Rasagiline Mesylate

Class: Monoamine Oxidase B Inhibitors
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

Introduction

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

Uses for Rasagiline Mesylate

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}

Rasagiline Mesylate 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 renal impairment.¹

Geriatric Patients

No dosage adjustment required.¹

Cautions for Rasagiline Mesylate

Contraindications

• 
  

  Concomitant use with cyclobenzaprine, dextromethorphan, meperidine, mirtazapine, methadone, propoxyphene, tramadol, St. John’s wort (Hypericum perforatum), sympathomimetic amines (e.g., amphetamines, ephedrine, phenylephrine, phenylpropanolamine [no longer commercially available in the US], pseudoephedrine), or other MAO inhibitors.¹ (See Interactions.)

  
  


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  Elective surgery that requires general anesthetics, cocaine, or local anesthetics containing sympathomimetic vasoconstrictors.¹ Discontinue rasagiline ≥14 days prior to elective surgery; if surgery is needed sooner, may use benzodiazepines, mivacurium, rapacuronium, fentanyl, morphine, or codeine with caution.^{1 8}

  
  


• 
  

  Pheochromocytoma.¹

  
  

Warnings/Precautions

Warnings

Risks Associated with MAO Inhibition

Selectivity for MAO-B (and not MAO-A) in humans not sufficiently elucidated to permit rasagiline treatment without restriction of dietary tyramine or sympathomimetic amines.¹ Even for relatively selective MAO-B inhibitors, selectivity for MAO-B usually diminishes and ultimately is lost at high dosages, and the drug will inhibit both MAO-B and MAO-A.¹

Possibly severe hypertensive reaction or hypertensive crisis (i.e., cheese reaction) following ingestion of foods, beverages, or dietary supplements containing large amounts of tyramine.¹ (See Interactions and see also Advice to Patients.)

Severe hypertensive reaction or hypertensive crisis reported following concomitant use of selective (i.e., selegiline) or nonselective (e.g., phenelzine, tranylcypromine) MAO inhibitors with sympathomimetic amines (e.g., ephedrine).¹ (See Interactions and see also Advice to Patients.)

Severe, sometimes fatal reactions resembling serotonin syndrome reported following concomitant use of selective or nonselective MAO inhibitors with highly serotonergic drugs (e.g., selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], SSRIs, tricyclic antidepressants).¹ (See 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.)

Major Toxicities

Orthostatic Hypotension

Orthostatic hypotension reported in patients receiving rasagiline as monotherapy or as adjunctive therapy with levodopa.¹ Occurs most frequently during the first 2 months of therapy and less frequently over time.¹

Hallucinations

Hallucinations reported in patients receiving rasagiline as monotherapy or as adjunctive therapy with levodopa.¹ (See Advice to Patients.)

General Precautions

Melanoma

Risk of melanoma developing^{4 5} in patients receiving rasagiline appears to be greater than that in the general population but comparable to that in patients with Parkinson’s disease.¹

Monitor for melanomas frequently.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 fall.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 ecchymosis,¹ somnolence,^{1 3} paresthesia.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}

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, SNRIs (e.g., duloxetine, venlafaxine)	Potential for serious, possibly fatal adverse effects (e.g., hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations of vital signs, extreme agitation, delirium, coma)1	Generally avoid concomitant use1 Allow ≥ 2 weeks to elapse between discontinuance of rasagiline and initiation of an SNRI 1
Antidepressants, SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline)	Potential for serious, possibly fatal adverse effects (e.g., hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations of vital signs, extreme agitation, delirium, coma) 1 2	Generally avoid concomitant use1 Allow ≥2 weeks to elapse between discontinuance of rasagiline and initiation of an SSRI1 Allow ≥5 weeks to elapse between discontinuance of fluoxetine and initiation of rasagiline; consider a longer interval in patients who received long-term or high-dosage fluoxetine therapy1
Antidepressants, tetracyclics (e.g., mirtazapine)		Concomitant use with mirtazapine is contraindicated1
Antidepressants, tricyclics (e.g., amitriptyline, protriptyline)	Potential for serious, possibly fatal adverse effects (e.g., behavioral and mental status changes, hyperpyrexia, diaphoresis, muscular rigidity, hypertension, syncope) 1 8	Generally avoid concomitant use1 Allow ≥2 weeks to elapse between discontinuance of rasagiline and initiation of a tricyclic antidepressant1
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 severe hypertensive reaction or hypertensive crisis1	Avoid foods, beverages, and dietary supplements containing large amounts of tyramine during and for 2 weeks following discontinuance of rasagiline1 (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, tramadol)	Potential for serious, possibly fatal adverse effects (resembling serotonin syndrome) (e.g., coma, severe hypertension or hypotension, severe respiratory depression, seizures, malignant hyperpyrexia, excitation, peripheral vascular collapse)1 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, phenylpropanolamine, pseudoephedrine)	Possible severe hypertensive reaction or hypertensive crisis1	Concomitant use with amphetamines, ephedrine, phenylephrine, phenylpropanolamine, or pseudoephedrine is contraindicated during and for 2 weeks following discontinuance of rasagiline1 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

Following daily administration for 7 days, AUC or peak plasma concentration of rasagiline was increased by 2- or 1.4-fold, respectively, in patients with mild (Child-Pugh score of 5–6) hepatic impairment and by seven- or twofold, respectively, in patients with moderate (Child-Pugh score of 7–9) hepatic impairment.¹ (See Hepatic Impairment under Dosage and Administration.)

Conclusive pharmacokinetic data in patients with renal impairment not available.^{1 8} However, because unconjugated rasagiline is not excreted by the kidneys, no dosage adjustment is necessary in patients with mild 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

ActionsActions

• 
  

  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) in humans not fully elucidated.¹ (See Risks Associated with MAO Inhibition under Cautions.)

  
  


• 
  

  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

• 
  

  Importance of recognizing tyramine content of foods, beverages, and dietary supplements, and avoiding those containing large amounts of tyramine (e.g., aged/fermented meat or cheese, pickled herring, pods of fava beans, sauerkraut, soy sauce, tofu, concentrated yeast extract, red wine, tap/draft beer) during and for 2 weeks following discontinuance of rasagiline.¹

  
  


• 
  

  Importance of avoiding OTC preparations containing sympathomimetic amines (e.g., ephedrine, phenylephrine, pseudoephedrine) during and for 2 weeks following discontinuance of rasagiline.¹

  
  


• 
  

  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 stroke) and promptly seeking medical attention if such manifestations occur.¹

  
  


• 
  

  Importance of informing clinicians promptly if hallucinations occur.¹

  
  


• 
  

  Risk of increased dyskinesia and orthostatic hypotension when used concomitantly with levodopa.¹

  
  


• 
  

  Importance of monitoring for melanomas frequently and receiving dermatologic examinations (i.e., performed by dermatologists) periodically.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 women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and/or herbal products (e.g., St. John’s wort), as well as any concomitant illnesses.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

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 03/2011. 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/$360 or 90/$979.95

Azilect 1MG Tablets (TEVA NEUROSCIENCE): 30/$346 or 90/$979.95

Disclaimer

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

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

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Teva Neuroscience, Inc. Azilect (rasagiline mesylate) tablets prescribing information. Teva Neuroscience, Inc. Kansas City, MO; 2006 May.

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. [PubMed 11159700]

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

a. AHFS drug information 2007. McEvoy GK, ed. Monoamine Oxidase Inhibitors General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2264-9.

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