Rasagiline …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 10.15.2021
Released 08.09.2005
Expires For CME 10.15.2024

Rasagiline

Author: K K Jain MD†

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Rasagiline

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Introduction

Historical note and terminology

Monoamine oxidase inhibitors were considered potentially useful in the treatment of Parkinson disease, as blocking its breakdown could enhance dopamine transmission. However, nonselective monoamine oxidase inhibitors did not prove beneficial when given as monotherapy, and hypertensive crises were a problem. It was then discovered that selegiline, as a selective monoamine oxidase type B inhibitor, did not produce this reaction and was the first product in this category to be approved for the treatment of Parkinson disease. Rasagiline is a potent, second-generation, selective, irreversible monoamine oxidase type B inhibitor. Unlike selegiline, a drug for Parkinson disease with a similar mechanism of action, rasagiline is not metabolized to amphetamine derivatives. In 2005, the European Commission gave the final marketing authorization for rasagiline for the treatment of Parkinson disease. It is marketed in Europe as Azilect. It was approved by the FDA in the United States in 2006 and in Japan in 2018.

Pharmacology

Rasagiline is N-propargyl-1-®aminoindan. Its main metabolite, aminoindan, improves motor and cognitive functions in experimental models and may, thus, contribute to the overall beneficial pharmacological profile of the drug.

Pharmacodynamics. Rasagiline completely, selectively, and irreversibly inhibits MAO-B with a potency 5 to 10 times greater than selegiline. MAO-B inhibition lasts at least 1 week after last dose. In clinical trials with patients with Parkinson disease, 25% to 35% MAO-B inhibition was achieved after a single rasagiline dose of 1 mg/day and multiple doses of rasagiline of 0.5, 1, and 2 mg per day resulted in complete MAO-B inhibition.

Rasagiline has the potential for a disease-modifying effect in Parkinson disease, in addition to its well-established symptomatic effect. It reduces the predominant levodopa-associated wearing-off phenomena, and complimentary combination with entacapone may support the concept of continuous nigrostriatal dopaminergic stimulation (18). The aminoindan metabolite of rasagiline has neuroprotective properties (01). The results of a study on a cell-line model indicate that rasagiline protects dopaminergic cells against free radical-mediated damage and apoptosis in the presence of alpha-synuclein over-expression (06). The mechanism of neuroprotective effect of rasagiline in Parkinson disease models was shown to be by prevention of the formation of reactive oxygen species derived from oxidation of dopamine by MAO-B and via an antiapoptotic action, which appears to be independent of MAO-B inhibition and related to its embedded N-propargyl moiety (32). Whether rasagiline is associated with clinically significant neuroprotection is the subject of ongoing clinical trials.

Pharmacokinetics. Rasagiline is absorbed from the gastrointestinal tract following oral administration and is presumed to cross the blood-brain barrier. The pharmacokinetic profile is as follows.

	• In the dose range of 1 to 6 mg, rasagiline demonstrates a more than proportional increase in area under the curve (AUC).
	• Peak plasma concentration (Cmax) is dose proportional and is reached in approximately 1 hour following the dose. The absolute bioavailability of rasagiline is about 36%.
	• Tissue binding of rasagiline is more than plasma protein binding, which ranges from 88% to 94%, with mean extent of binding of 61% to 63% to human albumin over the concentration range of 1 to 100 ng/mL.

Rasagiline is primarily metabolized to an active metabolite, 1-®-aminoindan, which shares some of the pharmacological actions of the parent compound.

A simple, rapid, and sensitive reverse-phase liquid chromatographic method has been developed and validated for estimation of rasagiline mesylate in different plasma matrices (26). This method can be used for determining pharmacokinetic parameters of rasagiline by noncompartmental analysis after oral dosing.

Transdermal rasagiline. In an open-label, randomized, parallel-group study on Chinese patients, a single-dose transdermal application of rasagiline prolonged t 1/2, increased AUC, and provided a more stable plasma drug concentration (34). Rasagiline patch may allow a longer dosing interval compared to the oral tablet.

Clinical trials

Results of well-designed clinical studies indicate that rasagiline is effective as initial monotherapy and improves symptomatology in patients with early Parkinson disease.

Table 1. Clinical Trials of Rasagiline

Study	Results
Double-blind, parallel-group, randomized, delayed-start clinical trial	• Patients treated with rasagiline for 12 months showed less functional decline than subjects whose treatment was delayed for 6 months (21).
The PRESTO study: a randomized, placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations	• The overall treatment benefit of rasagiline was statistically significant compared to placebo (22).
LARGO (Lasting effect in adjunct therapy with rasagiline given once daily): a randomized, double-blind, parallel-group trial of rasagiline as an adjunct to levodopa in patients with Parkinson disease and motor fluctuations	• Once-daily rasagiline reduced mean daily off-time and improved symptoms of Parkinson disease in levodopa-treated patients with motor fluctuations, an effect like that of entacapone (24).
Review of 2 multicenter, randomized, placebo-controlled, 26-week trials of rasagiline for early and moderate-to-advanced patients with Parkinson disease	• Rasagiline 1 mg once daily improves symptoms and motor fluctuations in early and moderate-to-advanced patients with Parkinson disease without causing significant cognitive and behavioral impairment (07).
ADAGIO study: a randomized, double-blind, placebo-controlled, early-start vs. delayed-start study to assess rasagiline as a disease modifying therapy in Parkinson disease	• Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not (20).
Additional secondary and post-hoc analyses of the ADAGIO study.	The rate of UPDRS deterioration was less than was anticipated from previous studies, and rasagiline delayed the need for symptomatic antiparkinsonian drugs (25).
A 15-week, multicenter, randomized, double-blind study to assess the safety and tolerability of rasagiline compared to the dopaminergic agonist pramipexole.	Rasagiline clinical efficacy as monotherapy for the treatment of early idiopathic Parkinson disease was comparable to pramipexole with lesser gastrointestinal and sleep adverse events (31).

The disease-modifying or neuroprotective effect of rasagiline is difficult to assess in late-start clinical trials because of its symptomatic effect on Parkinson disease.

Rasagiline, when used as adjunct therapy with levodopa in patients with moderate-to-advanced Parkinson disease in the phase 3 PRESTO and LARGO studies, was found to be safe as well as effective and benefited patients with signs of early wearing-off phenomenon (08). Data from clinical trials as well as review of literature suggest that rasagiline at an oral dose of 1 mg daily, used as monotherapy as well as adjunctive therapy, is effective for reducing tremor severity in patients with Parkinson disease (15). A single-blind study to evaluate the rapidity of onset effect of rasagiline on motor symptoms showed therapeutic effect from the first week of therapy, which further improved at 4 weeks without the need of a dose titration (33). A single-center, prospective, observational, 12-week study has concluded that addition of rasagiline to levodopa improves sleep outcomes and may be an option for patients with Parkinson disease experiencing sleep disorders (27).

A head-to-head, 3-year retrospective case-control study found that rasagiline and selegiline were equally efficient in controlling motor symptoms of patients with Parkinson disease on optimized therapy (03). A metaanalysis of various studies has concluded that rasagiline treatment is associated with significant improvement of UPDRS scores, which is not dose-dependent (04).

Indications

Rasagiline is indicated in the treatment of Parkinson disease, both as initial monotherapy in patients with early Parkinson disease and as adjunct to levodopa treatment in moderate-to-advanced Parkinson disease.

Off-label uses

	• Rasagiline has been shown to improve freezing in patients with primary progressive freezing gait.
	• A clinical trial in a parkinsonian variant of multiple system atrophy did not show efficacy (23).
	• Although some studies have reported a beneficial effect of rasagiline in depression associated with Parkinson disease, a randomized placebo-controlled trial did not show significant efficacy as compared to placebo (02). However, post hoc analyses showed some improvement in patient-rated depression outcomes.
	• In a placebo-controlled randomized phase 2 trial, use of rasagiline was safe as add-on therapy to riluzole in patients with amyotrophic lateral sclerosis; there was no difference between groups in the primary outcome of survival, but there was suggestion that rasagiline might have modified disease progression in a subgroup of patients, which needs further investigation (16). In a randomized, double-blind, placebo-controlled trial on patients with amyotrophic lateral sclerosis, there was no difference in the average 12-month ALS Functional Rating Scale-Revised slope between rasagiline and the mixed placebo and historical control cohorts (29). Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers.
	• Rasagiline has shown neuroprotective effect by delaying retinal degeneration in a mouse model of retinitis pigmentosa due to its action in increasing expression of antiapoptotic factor Bcl-2 and decreasing proapoptotic Bax (09).
	• Rasagiline monotherapy improves swallowing in patients with Parkinson disease (12).
	• Adjunctive rasagiline treatment may have beneficial effects on regional cerebral blood flow in patients with Alzheimer disease, suggesting potential neuroprotective effects (28). In a double-blind, parallel group, placebo-controlled, randomized to receive oral rasagiline or placebo (NCT02359552), FDG-PET was analyzed for the presence of an Alzheimer disease-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest (17). Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial.

References

01: Bar-Am O, Weinreb O, Amit T, Youdim MB. The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline. J Neurochem 2010;112(5):1131-7. PMID 20002521
02: Barone P, Santangelo G, Morgante L, et al. A randomized clinical trial to evaluate the effects of rasagiline on depressive symptoms in non-demented Parkinson's disease patients. Eur J Neurol 2015;22(8):1184-91. PMID 25962410
03: Cereda E, Cilia R, Canesi M, et al. Efficacy of rasagiline and selegiline in Parkinson's disease: a head-to-head 3-year retrospective case-control study. J Neurol 2017;264(6):1254-63. PMID 28550482
04: Chang Y, Wang LB, Li D, Lei K, Liu SY. Efficacy of rasagiline for the treatment of Parkinson's disease: an updated meta-analysis. Ann Med 2017;49(5):421-34. PMID 28293967
05: Chappell KB, Shah SP, Cutshall BT, Sands CW. Ciprofloxacin-rasagiline drug interaction leading to dopaminergic effects. Nurse Pract 2020;45(5):11-2.** PMID 32332227
06: Chau KY, Cooper JM, Schapira AH. Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells. Neurochem Int 2010;57(5):525-9. PMID 20624440
07: Elmer L, Schwid S, Eberly S, et al. Rasagiline-associated motor improvement in PD occurs without worsening of cognitive and behavioral symptoms. J Neurol Sci 2006;248(1-2):78-83. PMID 16828804
08: Elmer LW. Rasagiline adjunct therapy in patients with Parkinson's disease: post hoc analyses of the PRESTO and LARGO trials. Parkinsonism Relat Disord 2013;19(11):930-6. PMID 23849501
09: Garcia-Delgado AB, Valdés-Sánchez L, Calado SM, Diaz-Corrales FJ, Bhattacharya SS. Rasagiline delays retinal degeneration in a mouse model of retinitis pigmentosa via modulation of Bax/Bcl-2 expression. CNS Neurosci Ther 2018;24(5):448-55. PMID 29372592
10: Goren T, Adar L, Sasson N, Weiss YM. Clinical pharmacology tyramine challenge study to determine the selectivity of the monoamine oxidase type B (MAO-B) inhibitor rasagiline. J Clin Pharmacol 2010;50(12):1420-8. PMID 20445015
11: Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer-Attas CJ; TEMPO Open-label Study Group. Long-term outcome of early versus delayed rasagiline treatment in early Parkinson's disease. Mov Disord 2009;24(4):564-73. PMID 19086083
12: Hirano M, Isono C, Samukawa M, Fukuda K, Kusunoki S. Rasagiline monotherapy improves swallowing in patients with Parkinson's disease. Parkinsonism Relat Disord 2020;78:98-9.** PMID 32801070
13: Hoy SM, Keating GM. Rasagiline: a review of its use in the treatment of idiopathic Parkinson's disease. Drugs 2012;72(5):643-69. PMID 22439669
14: Keating GM, Lyseng-Williamson KA, Hoy SM. Rasagiline: a guide to its use in Parkinson's disease. CNS Drugs 2012;26(9):781-5. PMID 22834567
15: Lew MF. Rasagiline treatment effects on parkinsonian tremor. Int J Neurosci 2013;123(12):859-65. PMID 23767986
16: Ludolph AC, Schuster J, Dorst J, et al. Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial. Lancet Neurol 2018;17(8):681-8. PMID 29934198
17: Matthews DC, Ritter A, Thomas RG, et al. Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia. Alzheimers Dement (N Y) 2021;7(1):e12106.** PMID 33614888
18: Müller T. Pharmacokinetic/pharmacodynamic evaluation of rasagiline mesylate for Parkinson's disease. Expert Opin Drug Metab Toxicol 2014;10(10):1423-32. PMID 25196265
19: Nagai M, Hattori N. Pharmacological properties and clinical efficacy of rasagiline mesylate (Azilect®). [Japanese]. Nihon Yakurigaku Zasshi 2020;155(3):187-94. PMID 32378642
20: Olanow CW, Rascol O, Hauser R, et al. A double-blind delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009;361(13):1268-78. PMID 19776408
21: Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004;61(4):561-6. PMID 15096406
22: 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(2):241-8. PMID 15710852
23: Poewe W, Seppi K, Fitzer-Attas CJ, et al. Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol 2015;14(2):145-52. PMID 25498732
24: Rascol O, Brooks DJ, Melamed E, et al. 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. PMID 15766996
25: Rascol O, Fitzer-Attas CJ, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol 2011;10(5):415-23. PMID 21482191
26: Ravi PR, Aditya N, Cherian L, Patil S. LC method for determination of rasagiline mesylate in different plasma matrices and its application to oral pharmacokinetic study in rabbits. J Chromatogr Sci 2013;51(1):1-7. PMID 22689899
27: Schettino C, Dato C, Capaldo G, Sampaolo S, Di Iorio G, Melone MA. Rasagiline for sleep disorders in patients with Parkinson's disease: a prospective observational study. Neuropsychiatr Dis Treat 2016;12:2497-502. PMID 27729794
28: Song IU, Im JJ, Jeong H, Na SH, Chung YA. Possible neuroprotective effects of rasagiline in Alzheimer's disease: a SPECT study. Acta Radiol 2021;62(6):784-90.** PMID 32646230
29: Statland JM, Moore D, Wang Y, et al. Rasagiline for amyotrophic lateral sclerosis: a randomized, controlled trial. Muscle Nerve 2019;59(2):201-7. PMID 30192007
30: Valentino F, Cosentino G, Fierro B, et al. Pisa syndrome after rasagiline therapy in a patient with Parkinson's disease. Neurol Sci 2015;36(12):2305. PMID 26335016
31: Viallet F, Pitel S, Lancrenon S, Blin O. Evaluation of the safety and tolerability of rasagiline in the treatment of the early stages of Parkinson's disease. Curr Med Res Opin 2013;29(1):23-31. PMID 23176073
32: Weinreb O, Amit T, Riederer P, Youdim MB, Mandel SA. Neuroprotective profile of the multitarget drug rasagiline in Parkinson's disease. Int Rev Neurobiol 2011;100:127-49. PMID 21971006
33: Zambito Marsala S, Vitaliani R, Volpe D, et al. Rapid onset of efficacy of rasagiline in early Parkinson's disease. Neurol Sci 2013;34(11):2007-13. PMID 23636872
34: Zhou W, Lv C, Zhang Q, Zong S, Wang M. Pharmacokinetics, pharmacodynamics, and safety of rasagiline transdermal patch: a preliminary study in healthy Chinese subjects. Clin Drug Investig 2018;38(2):125-33. PMID 29159774

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Rasagiline

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Rasagiline …

Rasagiline

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Rasagiline

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
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Questions or Comment?

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Rasagiline

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Rasagiline

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Serotonin syndrome

Drug-induced myasthenic syndromes

Acupuncture

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

This is an article preview.
Start a Free Account
to access the full version.