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Std. Num.: 00126667 Type: Doc Del (Journal Article)
Publication: Drugs Genre: Journal Article
Publisher: Springer International Publishing [Cham]
Vol(Iss) Pg: 67 (12) p.1725-1747
Date 1/1/2007
Title: Rasagiline: A Review of its Use in the Management of Parkinson's Disease
Author(s): Oldfield, Vicki; Keating, Gillian M.; Perry, Caroline M.
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Drugs 2007; 67 (12): 1725-1747
ADIS DRUG EVALUATION 0012-6667/07/0012-1725/$49.95/0
© 2007 Adis Data Information BV. All rights reserved.
Rasagiline
THIS MANUSCRIPT IS PROVIDED IN CONFIDENCE TO DETERMINE REPRINT INTEREST ONLY AND SHOULD NOT BE DISTRIBUTED
A Review of its Use in the Management of

EITHER INTERNALLY OR EXTERNALLY VIA PRINT OR ELECTRONIC MEDIA FOR OTHER THAN THE STATED PURPOSE.
Parkinson’s Disease
Vicki Oldfield, Gillian M. Keating and Caroline M. Perry
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Health, Conshohocken, Pennsylvania, USA
Various sections of the manuscript reviewed by:

L. Elmer, Department of Neurology, Medical University of Ohio, Toledo, Ohio, USA; A. Hristova,
Department of Neurology, Columbia University Medical Center, New York, New York, USA; K. Kitani,
National Institute of Longevity Sciences, Obu, Aichi, Japan; M. Naoi, Department of Brain Sciences, Institute
of Applied Biochemistry, Gifu, Japan; B. Ravina, Neuroscience Center, National Institute of Neurological
Disorders and Stroke (NINDS), Rockville, Maryland, USA.
Data Selection
Sources: Medical literature published in any language since 1980 on ‘rasagiline’, identified using MEDLINE and EMBASE, supplemented
by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of
published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing
the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘rasagiline’ or ‘AGN-1135’ or ‘TVP-1012’. Searches were last
updated on 5 July 2007.
Selection: Studies in patients with Parkinson’s disease who received rasagiline. Inclusion of studies was based mainly on the methods
section of the trials. When available, large trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and
pharmacokinetic data are also included.
Index terms: Rasagiline, Parkinson’s disease, pharmacodynamics, pharmacokinetics, MAO-B inhibitor, therapeutic use, tolerability.
Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1726
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1728
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1728
2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1728
2.2 Neuroprotective Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1730
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1731
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1731
3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1731
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1732
4.1 As Monotherapy in Patients with Early Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1732
4.2 As Adjunctive Therapy in Patients with Moderate to Advanced Parkinson’s Disease and
Motor Fluctuations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1735
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1739
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1741
7. Place of Rasagiline in the Management of Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1742
1726 Oldfield et al.
Summary
Abstract Rasagiline (Azilect®) is a novel, selective, irreversible second-generation inhibi-
tor of monoamine oxidase type B (MAO-B). It is administered orally once daily
and is approved in the US, Canada, Mexico, Israel and the EU for use as
monotherapy and as adjunct therapy in the treatment of Parkinson’s disease.
Results of well designed clinical studies indicate that rasagiline is effective as

initial monotherapy and improves Parkinson’s symptomatology in patients with
early Parkinson’s disease. In addition, when administered in conjunction with
levodopa, in patients with moderate to advanced disease and motor fluctuations,
rasagiline reduces mean daily ‘off’ time and increases daily ‘on’ time without
troublesome dyskinesias, compared with controls. Rasagiline is generally well
tolerated as monotherapy and adjunctive therapy and is administered once daily.
Thus, rasagiline, administered as a simple and convenient dosage regimen, is a
well tolerated and effective option for monotherapy in patients with early Parkin-
son’s disease and for adjunctive therapy in patients with moderate to advanced
disease.
Pharmacological Rasagiline selectively and irreversibly inhibited MAO-B activity in a number of
Properties in vitro and in vivo studies. It was 5- to 10-fold more potent than selegiline at
inhibiting MAO-B activity in rats. The inhibition of MAO-B activity by rasagiline
is thought to lead to an increase in striatal extracellular dopamine levels and may
account for the beneficial effect of rasagiline treatment on motor function
observed in animal models of Parkinson’s disease.
Rasagiline has demonstrated neuroprotective activity in animal studies and in
vitro. Its main metabolite, 1-(R)-aminoindan has shown beneficial effects in vitro
and in vivo and does not inhibit the anti-apoptotic activity of rasagiline and has no
sympathomimetic effects, unlike the major selegiline metabolites, L-ampheta-
mine (L-amfetamine) and L-methamphetamine (L-metamfetamine), which are
neurotoxic and inhibit the neuroprotective activity of the parent drug.
In humans, oral rasagiline is rapidly absorbed, reaching a maximum plasma
concentration (Cmax) in ≤0.7 hours. Log Cmax was significantly correlated with
the percentage of platelet MAO-B inhibition in healthy volunteers. Rasagiline
undergoes extensive hepatic metabolism, with less than 1% of the dose being
eliminated in the urine unchanged. The main metabolites are 1-(R)-aminoindan,
3-hydroxy-N-propargyl-1-aminoindan and 3-hydroxy-1-aminoindan. Cmax and
the area under the plasma concentration-time curve increased by 2-fold and
7-fold, respectively, in patients with moderate hepatic impairment (Child-Pugh
score 7-9) compared with healthy individuals, following repeat dose administra-
tion for 7 days. The pharmacokinetic parameters of rasagiline in patients with
mild or moderate renal impairment are similar to those observed in healthy
volunteers.
Therapeutic Efficacy The therapeutic efficacy of oral once-daily rasagiline has been evaluated in three
large well designed clinical trials. Patients with early Parkinson’s disease received
rasagiline as early initial monotherapy in the TEMPO trial, which was designed to
evaluate the efficacy of rasagiline prior to treatment with dopaminergic agents
including levodopa. In the PRESTO and LARGO trials, patients with moderate to
advanced disease and motor fluctuations received rasagiline as an adjunct to
levodopa plus a dopa decarboxylase inhibitor.
© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (12)
Rasagiline: A Review 1727
In the TEMPO trial, the change from baseline in mean adjusted total Unified
Parkinson’s Disease Rating Scale (UPDRS) scores favoured rasagiline 1 or 2 mg/
day versus placebo recipients at 26 weeks and early-start rasagiline 1 or 2 mg/day
versus delayed-start (by 6 months) rasagiline 2 mg/day at 52 weeks. At 26 weeks,

the change from baseline in UPDRS motor, activities of daily living (ADL),
tremor and bradykinesia scores also significantly favoured rasagiline recipients,

and health-related quality of life (HR-QOL) remained stable with rasagiline.
Significantly more rasagiline 1 and 2 mg/day than placebo recipients responded to
treatment (experienced a <3-unit increase in total UPDRS score) at 26 weeks. To
date, rasagiline therapy has been shown to adequately control Parkinson’s symp-
toms in the long term (6.5 years) and the beneficial effect of early- versus delayed-
start rasagiline was maintained during this period.
Rasagiline 0.5 and 1 mg/day together with levodopa and other antiparkinsoni-
an therapy significantly decreased the amount of daily ‘off’ time (primary
endpoint) compared with placebo in the PRESTO (0.5 and 1 mg/day) and
LARGO (1 mg/day) trials. Additionally, compared with placebo, rasagiline
recipients had significantly improved Clinical Global Impression (CGI) scores,
UPDRS ADL scores during ‘off’ time and UPDRS motor scores during ‘on’ and
‘off’ time. Levodopa-responsive symptoms, including tremor, rigidity and
bradykinesia, improved with rasagiline, improving ‘on’ time without troublesome
dyskinesias and the response to treatment (≥1 hour decrease in mean total daily
‘off’ time) was significantly greater with rasagiline than placebo in the LARGO
trial. Rasagiline treatment had no effect on HR-QOL in the more advanced
Parkinson’s disease patients in the PRESTO trial.
Tolerability Rasagiline was generally well tolerated as monotherapy in patients with early
Parkinson’s disease. The most frequently occurring adverse events in rasagiline
recipients during the first 26 weeks of the TEMPO trial were infection and
headache. During the long-term TEMPO extension (up to 6.5 years) rasagiline
was well tolerated with the most common adverse events reported being infection
and accidental injury.
Rasagiline was also generally well tolerated when added to other antiparkin-
sonian medication in patients with moderate to advanced disease and motor
fluctuations, with the most commonly occurring adverse events being
dopaminergic related. The incidence of dopaminergic adverse events was similar
with rasagiline and placebo in the LARGO trial, but in the PRESTO trial
rasagiline recipients reported a significantly greater incidence of weight loss,
vomiting, anorexia, balance difficulty and dyskinesias. Depression occurred sig-
nificantly less frequently with rasagiline than with placebo in the PRESTO trial.
Serious adverse events with rasagiline were infrequent and rasagiline treatment
had little or no effect on ECG recordings, blood pressure, heart rate or laboratory
measurements. No increase in sensitivity to tyramine was observed following a
tyramine challenge performed in subpopulations of patients at the end of the
TEMPO and PRESTO trials. All three trials were without dietary tyramine
restrictions and no cases of hypertensive crisis were reported. Discontinuation
rates due to adverse events were low.
1. Introduction dysfunction and dementia, develop as the disease

progresses.[9]
Parkinson’s disease is a progressive Other antiparkinsonian agents, such as dopamine
neurodegenerative disease that is characterised by agonists and monoamine oxidase type B (MAO-B)
the symptoms of resting tremor, rigidity, bradykine- inhibitors, are used as monotherapy as alternatives
sia and postural instability.[1,2] After Alzheimer’s to levodopa and may be used instead of, or in
disease, it is the second most common neurodegen- conjunction with, levodopa in patients with moder-
erative disease; Parkinson’s disease affects approxi- ate to advanced disease.[2,9] Catechol-O-methyl
mately 1–2% of the European population over the transferase (COMT) inhibitors are frequently ad-
age of 65 years,[3] and the prevalence increases to ministered with levodopa to alleviate levodopa-re-
2–3% in those aged 85–89 years.[1,3] In the US, the lated motor fluctuations.[2]
prevalence of Parkinson’s disease was estimated to MAO-B is the major enzyme responsible for the
be 1 200 000 in 2005 and is predicted to reach metabolism of dopamine in the human brain and
1 860 000 in 2015. Similarly, an increase in the inhibition of its activity helps to conserve the supply
prevalence of Parkinson’s disease, from 240 000 in of dopamine.[10] Until recently, selegiline was the
2005 to 370 000 in 2015, has been predicted in the only approved MAO-B inhibitor for use in the treat-
UK.[4] ment of Parkinson’s disease and, in the US, was only
Although several contributing factors have been approved as adjunctive therapy to levodopa.
identified, the underlying aetiology of Parkinson’s Rasagiline (Azilect®)1 is a novel, selective, irre-
disease remains unknown.[5] The pathogenesis of the versible, second generation inhibitor of MAO-B that
disease is thought to involve necrosis and/or has recently been approved in the US, Canada, Mex-
apoptosis of dopaminergic neurons,[5,6] and clinical ico, Israel and the EU for use as initial monotherapy
signs of Parkinson’s disease appear when approxi- in early Parkinson’s disease and as adjunctive ther-
mately 80% of striatal dopamine and 50% of nigral apy to levodopa in moderate to advanced Parkin-
neurons are lost.[2] Current pharmacological, surgi- son’s disease.[11,12] This article reviews the use of
cal and rehabilitative therapeutic approaches are rasagiline as monotherapy or as adjunctive therapy
palliative only and have not been shown to halt or in combination with levodopa in patients with
slow disease progression. Parkinson’s disease. The pharmacology and clinical
Treatment of Parkinson’s disease is usually initi- profile of rasagiline have been reviewed previously
ated when functional disability or an impact on in Drugs & Aging.[13]
quality of life is evident and is individualised ac-
cording to the patient’s symptoms.[7] There is, how- 2. Pharmacodynamic Properties
ever, a growing trend to initiate treatment at an early
Rasagiline selectively inhibits the activity of
stage of the disease.[8] The definition of functional
MAO-B and is consequently thought to have an-
impairment (FI) is highly variable and dependent on
tiparkinsonian properties. It has also demonstrated
individual patient characteristics, including age and
neuroprotective properties in in vitro and in vivo
vocation. Levodopa, the precursor of dopamine,
experiments that are independent of its MAO-B
forms the backbone of therapy for Parkinson’s dis-
inhibitory activity. The pharmacodynamic proper-
ease (although not at early stages). However, within
ties of rasagiline are summarised in table I.
5 years of starting levodopa treatment, up to 50% of
patients experience levodopa-related motor fluctua-
2.1 Mechanism of Action
tions such as ‘wearing-off’ and ‘on-off’ effect.[2]
Other symptoms that are not adequately controlled Rasagiline selectively inhibited MAO-B in a
by levodopa, such as freezing of gait, autonomic number of in vitro[14] and in vivo[14,16-23] studies
1 The use of trade names is for product identification purposes only and does not imply endorsement.
Table I. Overview of the pharmacodynamic properties of rasagiline

MAO-B inhibition
Selectively and irreversibly inhibited MAO-B activity in human brain tissue, and rat liver and brain tissue in vitro[14] and in vivo[15] in
patients with Parkinson’s disease,[15,16] healthy volunteers[17] and animals[14,18-23]
5- to 10-fold more potent than selegiline in inhibiting MAO-B activity in vivo in the rat brain and liver[14]
Antiparkinsonian and motor restoration effects

Increased dopamine in ex vivo rat striatal tissue (p < 0.01 vs control)[24]
Increased striatal extracellular dopamine following administration of a bolus of L-DOPA in rhesus monkeys (p < 0.01 vs control)[19]
Prevented MPTP-induced loss of neostriatal dopamine in mice[25]
Attenuated the decline in spontaneous motor activity and increase in development of Parkinsonian signs (according to a non-human
primate Parkinson’s disease rating scale) in an MPTP-induced model of Parkinson’s disease in the marmoset (p ≤ 0.05 vs control)[18]
Neuroprotective effects
Effect on dopaminergic neurons
Significantly increased survival of total and dopaminergic neurons in fetal rat[26,27] and human[27] ventral mesencephalon (p < 0.05 vs
control for each comparison) in vitro
Significantly reduced the loss of dopaminergic neurons in the ex vivo rat substantia nigra following administration of the apoptosis-
inducing neurotoxin 6-OHDA (p < 0.002 vs control)[28]
Effect on recovery of motor function
Significantly accelerated recovery of motor function following closed head injury in mice (p < 0.05 vs control)[29] and α-MpT-induced
hypokinesia and haloperidol-induced catalepsy in rats and mice (p ≤ 0.05 vs control for each comparison)[21]
Significantly reduced cerebral oedema after closed head injury in mice (p < 0.05 vs control)[29]
Effect on apoptotic cell death
Protected against apoptotic cell death in NGF-differentiated PC12 cells deprived of oxygen and glucose,[30,31] serum[32] or NGF[33,34]
Protected against apoptosis in cultured human dopaminergic neuroblastoma SH-SY5Y cells exposed to the apoptosis inducers
6-OHDA, N-M-(R)-Sal or SIN-1[35-37]
Protected against glutamate,[38,39] Ara-C[39] and BSO[39] toxicity in rat hippocampal neurons[38] and in rat cerebellar granule cells[39]
Reduced paraventricular hypothalamic neurodegeneration in a rat model[40] and, in combination with riluzole, prolonged survival and
improved motor function in a mouse model of familial amyotrophic lateral sclerosis[41]
Improved neurological severity score and decreased the volume of necrotic brain tissue compared with saline after permanent middle
cerebral artery occlusion in the rat[42]
Effect on mechanisms of apoptosis
Prevented pre-apoptotic decline in ∆Ψm,[34,35,37,43] chromatin condensation,[34] release of cytochrome c[37] and activation of
caspase-3[35,43] (activates DNAase and cleaves DNA during apoptosis) in dopaminergic neuroblastoma SH-SY5Y cells exposed to N-M-
(R)-Sal, 6-OHDA or SIN-1
Prevented a decrease in the anti-apoptotic enzymes Bcl-2 and SOD in response to serum and NGF withdrawal from PC12 cells in
vitro,[34] and significantly increased activity of catalase and SOD in the rat substantia nigra and striatum in vivo (p < 0.05 vs control)[44]
Significantly increased the expression of p-PKC(pan) and the α and ε PKC isozymes (regulators of apoptosis)[32,45] and pMARCKS (a
substrate for PKC)[45] in PC12 cells[32] and mouse hippocampus[45] (both p < 0.05 vs control)
6-OHDA =6-hydroxydopamine; α-MpT = α-methyl-p-tyrosine; ∆Ψm = mitochondrial membrane potential; Ara-C = cytosine β-D-
arabinofuranoside; BSO = L-buthionine-(S,R)-sulphoximine; L-DOPA = levodopa; MAO-A = monoamine oxidase type-A; MAO-B =
monoamine oxidase type-B; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NGF = nerve growth factor; N-M-(R)-Sal = N-methyl-
(R)-salsolinol; PC12 = rat phaeochromocytoma cells; PKC = protein kinase C; pMARCKS = phosphorylated myristoylated alanine-rich C
kinase substrate; p-PKC(pan) = phosphorylated pan-PKC; SH-SY5Y = human dopaminergic cells expressing only MAO-A, not MAO-B;
SIN-1 = N-morpholine sydnonimine; SOD = superoxide dismutase.
(table I). Rasagiline was 5- to 10-fold more potent approximately 35%, 55%, 79% and 99%, respec-
(p < 0.05) than selegiline at inhibiting MAO-B tively; all p < 0.05 vs placebo).[17] With repeated
activity in vivo (table I).[14] With single doses of administration of rasagiline 2 mg/day, almost com-
rasagiline 1, 2, 5 or 10mg, maximal inhibition of plete (>99%) MAO-B inhibition was achieved on
platelet MAO-B activity (a marker for brain MAO- day 6.[17] In this study, the percentage of MAO-B
B activity) was observed 1 hour after administration inhibition correlated with the log of the maximum
in healthy volunteers (MAO-B activity inhibited by plasma concentration (Cmax) of rasagiline (correla-
tion coefficient = 0.79, p < 0.001) [section 3].[17] In ous locomotor activity and increase in Parkinsonian
human brain tissue in vitro, the rasagiline concentra- signs (according to a non-human primate Parkin-
tion inhibiting MAO-B activity by 50% (IC50) was sonian rating scale).[18]
14 nmol/L, compared with 710 nmol/L for inhibi-

tion of MAO-A activity; corresponding IC50 values 2.2 Neuroprotective Effects
for inhibition of MAO-B and MAO-A by selegiline

were 6.8 and 1700 nmol/L, respectively.[14] Rasagiline has demonstrated neuroprotective
properties in vivo in animal models of neuronal
The inhibitory activity of rasagiline is irreversi-
degeneration[28,40,41,48] and in response to focal is-
ble.[15,17] A decrease in MAO-B activity was ob-
chemia[42] and head injury[29] (table I). It has also
served in the thalamus and basal ganglia immediate- demonstrated neuroprotective activity in vitro in
ly after the last dose of rasagiline in healthy volun- fetal rat[26,27] and human[27] ventral mesencephalon
teers who received rasagiline 1 mg/day for 10 days and in response to neurotoxins[21,35,36,38] and oxygen/
and recovery of MAO-B activity in these areas glucose, serum or nerve growth factor depriva-
occurred gradually over 6 weeks, consistent with tion[30-34] (table I). The neuroprotective effect of
reports that the half-life for de novo synthesis of rasagiline is independent of its MAO-B inhibitory
MAO-B is 40 days.[15,46] In another study in healthy activity.[34-36] Indeed, some of the neuroprotective
human volunteers,[17] maximum inhibition of MAO- effects of rasagiline have been seen in cell lines and
B activity was maintained for at least 48 hours primary neurones that express only the MAO-A
following administration of a single dose of isoenzyme.[35,37,49-51] Furthermore, the (S)-enanti-
rasagiline 1–10mg and a significant difference in omer of rasagiline, which lacks MAO-inhibitory
MAO-B inhibition was evident with rasagiline com- activity, has also shown protective effects in vitro
pared with placebo 7 days after administration of and in vivo.[29,35,39,52,53] Thus, the neuroprotective
rasagiline 10mg (p < 0.05). Platelet MAO-B activity effects of rasagiline cannot be attributed in the main
returned to normal 14 days after rasagiline adminis- to its inhibition of MAO-B. Structure-activity stud-
tration in this study.[17] ies have shown that this activity is associated with
Inhibition of MAO-B activity by rasagiline is the propargyl moiety of rasagiline.[54]
thought to cause an increase in extracellular striatal The neuroprotective activity of rasagiline may be
dopamine levels; administration of rasagiline 0.5–5 due to its ability to inhibit apoptosis, which has been
mg/kg/day for 21 days produced significant in- demonstrated in various in vitro studies,[30-36,38] and
creases in dopamine levels in extracellular striatal is thought to be the result of inhibition of the
rat[24] and monkey[19] tissue (table I). Corresponding apoptotic cascade initiated by mitochondria involv-
decreases in the levels of the dopamine metabolites, ing interaction with protein kinase C isozymes and
3,4-dihydroxyphenylacetic acid (DOPAC) and upregulation of anti-apoptotic Bcl-2 family proteins
homovanillic acid (HVA), observed in some stud- (table I).[32,34,35,37,43-45]
ies,[18,24] suggest that the increase in dopamine levels Unlike the major selegiline metabolites, L-am-
is the result of inhibition of MAO metabolism of phetamine (L-amfetamine) and L-metham-
dopamine by rasagiline. Additional mechanisms of phetamine (L-metamfetamine), which are neurotox-
action have been suggested, including accumulation ic and inhibit the neuroprotective activity of the
of endogenous beta-phenylethylamine.[47] Increased parent drug, the major metabolite of rasagiline, 1-
dopamine levels may account for the beneficial ef- (R)-aminoindan, does not inhibit the anti-apoptotic
fects of rasagiline treatment on motor function ob- activity of rasagiline and has no sympathomimetic
served in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropy- activity.[33,55] 1-(R)-aminoindan did not potentiate
ridine (MPTP)-induced model of Parkinson’s dis- oxygen-glucose deprivation-induced cell death in
ease in the marmoset; rasagiline treatment rat nerve growth factor-differentiated phaeochromo-
attenuated the MPTP-induced decline in spontane- cytoma (PC12) cells, compared with L-
methamphetamine, which increased cell death by Table II. Mean pharmacokinetic properties of single-[17] and multi-
ple-dose[16,17] once-daily oral rasagiline (RAS) in healthy volun-
≈70%.[30] In rats, L-methamphetamine was associat- teers[17] and patients with Parkinson’s disease as an adjunct to
ed with dramatic reductions in mean arterial pres- levodopa.[16] Pharmacokinetic parameters were measured at day 1
sure and carotid blood flow and an increase in (single dose) and after 10 days of administration in healthy volun-
teers (n = 24),[17] and after 12 weeks of treatment in patients with
carotid vascular resistance (all p < 0.05 vs baseline), Parkinson’s disease (n = 70)[16]
whereas 1-(R)-aminoindan induced much milder Parameter Healthy Patients with Parkinson’s
changes in these parameters.[55] 1-(R)-aminoindan volunteers[17] disease[16]
has also demonstrated neuroprotective activity in RAS RAS RAS RAS RAS
vitro[33] and, although it is not a MAO inhibitor, it 2mg SD 2 mg/day 0.5 mg/ 1 mg/day 2 mg/day
MD day MD MD MD
was more active than rasagiline in preventing α- Cmax 9.55 17.55 4.2 8.5 14.9
methyl-p-tyrosine-induced hypokinesia in hypoxia- (ng/mL)
lesioned adult rats.[21] tmax (h) 0.36 0.40 0.5–0.7a 0.5–0.7a 0.5–0.7a
AUC 5.85b 20.02**c 6.4d 12.4d 23.5d
3. Pharmacokinetic Properties (ng • h/mL)
CLR (L/h) 1.11 0.56*
The pharmacokinetic data presented in this sec- t1/2 (h) 2.06
tion have been sourced from studies in healthy vol- a Values apply across the range 0.5–2 mg/day.
unteers[17] and patients with Parkinson’s dis- b From time zero to infinity.
ease[16,56] receiving oral rasagiline at dosages of up c From time zero to 24 hours.
d From time zero to an unspecified time.
to 4 mg/day. Additional data have been sourced
AUC = area under the plasma concentration-time curve; CLR =
from the prescribing information.[11,12] renal clearance; Cmax = maximum plasma concentration; MD =
The pharmacokinetic properties of rasagiline are multiple doses; SD = single dose; t1/2 = half-life; tmax = time to Cmax;
summarised in table II.[16,17] The effect of hepatic * p < 0.05, ** p < 0.001 vs 2mg SD.
impairment on rasagiline pharmacokinetics is dis-

cussed in section 3.1.[11] also increased linearly in proportion to the rasagiline
dosage over the range 0.5–10 mg/day.[16,17,56] Cmax
3.1 Absorption and Distribution and the AUC increased by 2-fold and 7-fold, respec-
Rasagiline reached a Cmax in a time (tmax) of ≤0.7 tively, in patients with moderate hepatic impairment
hours (table II) following oral administration of (Child-Pugh score 7-9) compared with healthy indi-
single or multiple 0.5–2mg doses in healthy volun- viduals, following repeat dose administration for 7
teers and in patients with Parkinson’s disease.[16,17] days.[12] Rasagiline is contraindicated in patients
Rapid absorption of rasagiline is consistent with the with severe hepatic insufficiency and use in patients
observation that MAO-B inhibition occurs within 1 with moderate hepatic insufficiency should be
hour of administration of rasagiline, since log Cmax avoided.[11,12]
correlated with the percentage of platelet MAO-B The mean volume of distribution (Vd) ranged
inhibition in healthy volunteers (section 2.1).[17] The from 182L for oral rasagiline 4 mg/day in patients
absolute bioavailability following a single dose of with Parkinson’s disease[56] to 243L for intravenous
oral rasagiline is ≈36%.[11] rasagiline.[11] A steady-state Vd of 87L has also been
The area under the plasma concentration-time reported.[10] Rasagiline is 60–70% plasma protein-
curve (AUC) was significantly higher (p < 0.001) bound after a single oral dose.[11]
after administration of rasagiline 2 mg/day for 10
days than after administration of a single 2mg dose 3.2 Metabolism and Elimination
(table II).[17] This increase may reflect the binding of
rasagiline to MAO-B sites; after saturation of MAO- Rasagiline is metabolised in the liver, where it
B sites, rasagiline concentrations should remain undergoes nearly complete biotransformation to
constant with repeat administration. AUC and Cmax yield the metabolites 1-(R)-aminoindan (the major
active metabolite [section 2]), 3-hydroxy-N- observed in healthy volunteers; dosage modification
propargyl-1 aminoindan and 3-hydroxy-1-ami- is therefore not required for such patients.[11]
noindan.[11,12] 1-(R)-aminoindan is present in plasma
at a lower concentration than the parent drug and the 4. Therapeutic Efficacy
Cmax and AUC for 1-(R)-aminoindan increase pro-
Three large (n > 400 per study) randomised,

portionally when the rasagiline dosage in- double-blind, parallel-group, multicentre clinical tri-
creases.[16,17,56] Unlike selegiline,[57] rasagiline is not als have evaluated the efficacy of once daily oral
metabolised to amphetamine or amphetamine deriv- rasagiline in patients with early Parkinson’s disease
atives.[11] who received rasagiline as their first treatment (sec-
The two main pathways of rasagiline metabo- tion 4.1)[58] and in patients with moderate to ad-
lism, N-dealkylation and hydroxylation, are depen- vanced disease and motor fluctuations who received
dent on the cytochrome P450 (CYP) system.[11,12] In rasagiline as adjunctive therapy (section 4.2).[59,60]
particular, the major isoenzyme involved in Preliminary evidence for the efficacy of
rasagiline metabolism is CYP1A2; therefore, rasagiline in the treatment of Parkinson’s disease
coadministration of rasagiline with a CYP1A2 in- was found in two small, randomised, double-blind,
hibitor, such as ciprofloxacin, is contraindicated in parallel-group, placebo-controlled, multicentre tri-
Europe.[11] In the US, the dosage of rasagiline als in patients with early disease who received
should be reduced to 0.5mg daily in patients taking rasagiline 1–4 mg/day as monotherapy (n = 56)[56]
concomitant ciprofloxacin or other CYP1A2 inhibi- and in patients with moderate to advanced disease
tors. [12] In vitro studies showed that rasagiline did who received rasagiline 0.5–2 mg/day in addition to
not inhibit CYP1A2, CYP2A6, CYP2C9, levodopa (n = 70).[16] The results of these two pub-
CYP2C19, CYP2D6, CYP2E1, CYP3A4 or lished trials are not discussed further.
CYP4A.[11]
4.1 As Monotherapy in Patients with Early
The terminal half-life (t1/2) of rasagiline is inde- Parkinson’s Disease
pendent of the dose[56] and ranged from 0.6 to 2
hours following administration of rasagiline The efficacy of rasagiline monotherapy, adminis-
0.5–2mg (route of administration not specified).[11] tered once daily, was evaluated for 6 months in
Following oral administration of rasagiline 2 mg/ patients with early Parkinson’s disease in the TEM-
day for 10 days in healthy volunteers, the mean t1/2 PO (TVP-1012 in Early Monotherapy for Parkinson
was 2.06 hours (table II).[17] The mean steady-state disease Outpatients) trial.[58] This trial was designed
to evaluate the efficacy of rasagiline prior to treat-
t1/2 of rasagiline is 3 hours[12] in patients with Parkin-
ment with dopaminergic agents including levodopa.
son’s disease.[10]
There were no dietary tyramine restrictions. This
Elimination of rasagiline is primarily via urine, trial also assessed the effect of early- versus
where less than 1% of the rasagiline dose is excreted delayed-start rasagiline monotherapy after 12
unchanged.[11] Following oral administration of 14C- months of treatment[61] and results are available for
labelled rasagiline, 84.4% of the dose was recovered up to 6.5 years of treatment in the ongoing open-
over a period of 38 days: 62.6% was eliminated via label follow-up period.[62,63]
urine and 21.8% via faeces.[11] The renal clearance Patients enrolled in the TEMPO trial (n = 404)
(CLR) of rasagiline decreases with repeat adminis- were aged >35 years with at least two of the cardinal
tration; the CLR of rasagiline 2 mg/day at day 10 signs of Parkinson’s disease and maximum disease
was significantly lower than at day 1 in healthy severity of Hoehn and Yahr stage III.[58] In the initial
volunteers (p < 0.05) [table II].[17] The pharmacoki- double-blind, placebo-controlled phase, patients
netic parameters of rasagiline in patients with mild were randomised to receive rasagiline 1 or 2 mg/day
or moderate renal impairment are similar to those or placebo for 26 weeks.[58] At 26 weeks, placebo
recipients were switched to rasagiline 2 mg/day months and long-term results were reported for all
(delayed-start rasagiline) while other rasagiline re- patients treated with rasagiline during any phase of
cipients continued their originally randomised treat- the trial (n = 398)[62] and for the ITT population of
ment for another 26 weeks in the second, double- patients (n = 404) in the ongoing phase of the trial
blind treatment phase.[61] During the subsequent, only.[63]
open-label, follow-up period, all patients were Secondary endpoints evaluated in the first and
switched to rasagiline 1 mg/day.[63] Additional an- second double-blind phases of the trial included
tiparkinsonian medication (levodopa and/or changes in the mental, activities of daily living
dopamine agonists) was added as required. Long- (ADL) and motor UPDRS subscale scores; symp-
term results following administration of rasagiline tom-based tremor, rigidity, bradykinesia and postur-
for up to 6.5 years (data available as abstracts and al instability/gait disorder UPDRS subscores;
posters only) have been presented for a single cohort changes in the Parkinson’s disease quality-of-life
of all patients treated with rasagiline at any time[62] (PD-QUALIF) scale; and the proportion of respond-
and for the early- versus delayed-start treatment ers to treatment (those patients who experienced a
groups.[63] worsening in the total UPDRS of <3 units from
The primary efficacy outcome of the TEMPO baseline to 26 weeks[58] or a worsening of <4 units
trial was the change from baseline in the total Uni- over the 12-month study period[61]).
fied Parkinson’s Disease Rating Scale (UPDRS) Baseline total UPDRS scores were similar for the
score at 26[58] and 52[61] weeks. Results for the rasagiline 1 and 2 mg/day and placebo treatment
initial, placebo-controlled phase were reported for groups (24.7, 25.9 and 24.5, respectively).[58]
the intention-to-treat (ITT) population which includ- UPDRS motor, ADL, mental and bradykinesia sub-
ed all randomised patients.[58] Results for the second scale scores and PD-QUALIF scores were also simi-
phase were reported for patients with at least one lar between treatment groups at baseline (17.6–18,
post-randomisation measurement, using last obser- 5.9–6.7, 0.8–1.2, 7.8–8.3 and 26.9–30.2, respective-
vation carried forward (LOCF) analysis where data ly).[58]
were missing or incomplete.[61] The adjusted effect Rasagiline as initial monotherapy was effective
size was the between-group difference in the mean in patients with early Parkinson’s disease[58,61] sig-
total UPDRS score change from baseline for nificantly improving motor function and other
rasagiline 1 or 2 mg/day versus placebo at 26 weeks Parkinsonian symptoms at 26 weeks (table III).[58,64]
(n = 404)[58] and versus delayed-start rasagiline at 52 Beneficial effects were also reported after 52 weeks
weeks (n = 371),[61] adjusted for baseline UPDRS of treatment with rasagiline.[61,65] The change from
score, centre, treatment and centre-treatment inter- baseline in mean adjusted total UPDRS scores
action. During the open-label follow-up period, favoured rasagiline 1 or 2 mg/day versus placebo at
UPDRS assessments were conducted every 3 26 weeks (p < 0.0001)[58] and rasagiline 1 mg/day (p
Table III. Efficacy of oral rasagiline (RAS) monotherapy in patients with early Parkinson’s disease. In the initial, placebo-controlled phase of
the double-blind TEMPO trial, patients were randomised to receive RAS 1mg or 2mg or a matching placebo (PL) once daily for 26 weeks.[58]
Parkinson’s disease symptomatology was assessed using the UPDRS and its component subscales and health-related quality of life was
measured using the PD-QUALIF scale. Data shown are 26-week results in the intention-to-treat population (data on file)[64]
Comparison regimens Adjusted mean change from baseline in UPDRS scores Adjusted mean change
(no. of patients) total motor ADL mental tremor rigidity bradykinesia from baseline in PD-
QUALIF score
RAS 1mg (n = 134) –0.13*** –0.38*** 0.16** 0.15 –0.10** 0.02 –0.54*** –0.36*
RAS 2mg (n = 132) 0.51*** 0.65** –0.02*** 0.03 0.15 0.02 0.19* –0.19*
PL (n = 138) 4.07 2.33 1.20 0.29 0.53 0.41 0.96 2.55
ADL = activities of daily living; PD-QUALIF = Parkinson’s Disease quality of life; UPDRS = Unified Parkinson’s Disease Rating Scale;
* p < 0.05, ** p ≤ 0.005, *** p < 0.0001 vs PL.
a 26 weeks RAS 1 mg/day

= 0.05) or 2 mg/day (p = 0.01) versus delayed-start
adjusted UPDRS scores relative to placebo (95%CI)

1 RAS 2 mg/day
rasagiline at 52 weeks;[61] between-group differ-
Differences in change from baseline in mean

ences are shown in figure 1 (a decrease in UPDRS 0
score indicates an improvement of symptoms). Both

univariate analysis and repeated measures analysis −1
confirmed that significantly less disease progression *

−2 *
occurred in patients who received rasagiline 1 or 2
mg/day for 52 weeks compared with patients who −3 *
had their treatment deferred for 26 weeks.[65] Benefi-
cial effects on disease symptoms were initially evi- −4 *
dent after 4 weeks of treatment.[65]
−5
The change from baseline in UPDRS motor, **
ADL, tremor and bradykinesia subscores also sig- −6 **
nificantly favoured rasagiline.[58,61] At 26 weeks, the
change from baseline in the mean adjusted UPDRS
UPDRS scores relative to delayed-start RAS 2 mg/day (95%CI)
motor and ADL scores with rasagiline 1 and 2 mg/ b 52 weeks

Differences in change from baseline in mean adjusted
day indicated that worsening of symptoms was sig- 1

nificantly less with rasagiline than with placebo;
between-group differences are shown in figure 1[58] 0
and changes from baseline are shown in table III (p

−1
≤ 0.005 for each comparison).[64] The between-
group difference in the change from baseline in the −2 ‡
mean adjusted bradykinesia score at 26 weeks was
–1.51 (95% CI –2.19, –0.82 ) for rasagiline 1 mg/ −3
day versus placebo and –0.77 (95% CI –1.47, –0.08)
for rasagiline 2 mg/day versus placebo (p < 0.001 −4 †
for each comparison).[58] The between-group differ- ††

ence in the change from baseline in the mean adjust- −5
ed tremor score at 26 weeks was –0.63 (95% CI

−6
–1.03, –0.23) for rasagiline 1 mg/day versus placebo
Total Motor ADL Mental
(p < 0.05) and –0.38 (95% CI –0.78, 0.02) for UPDRS scores
rasagiline 2 mg/day versus placebo. Treatment with
rasagiline had no significant effect on the UPDRS Fig. 1. Efficacy of oral rasagiline (RAS) monotherapy in patients
mental score (figure 1).[58,61] At 52 weeks, there was with early Parkinson’s disease. In the double-blind TEMPO trial,
patients were randomised to receive RAS 1mg (n = 134) or 2mg
a significant between-group difference in the change (n = 132) once daily or a matching placebo (n = 138) for 26 weeks
from baseline in the mean adjusted UPDRS ADL (placebo-controlled phase).[58] At 26 weeks, patients in the placebo
score for rasagiline 2 mg/day compared with group were switched to RAS 2 mg/day (delayed-start rasagiline)
[n = 130] while all other patients continued their original treatment
delayed-start rasagiline 2 mg/day (–0.96; p = 0.005; (RAS 1 mg/day [n = 122] or 2 mg/day [n = 119]) for an additional 26
figure 1).[61] weeks (active-treatment phase).[61] Parkinson’s disease symptoma-
tology was assessed using the Unified Parkinson’s Disease Rating
In a post hoc analysis performed on the 26-week Scale (UPDRS) and its component subscales. The between-group
placebo-controlled phase of the TEMPO study, in differences in the change from baseline in mean adjusted UPDRS
which the size of effect of treatment with rasagiline scores are depicted for RAS 1 or 2 mg/day treatment groups rela-
tive to (a) placebo[58] or (b) delayed-start RAS 2 mg/day.[61] ADL =
1 mg/day was assessed in relation to the severity of activities of daily living; * p < 0.05, ** p < 0.001 vs placebo; † p =
Parkinson’s disease at baseline, the symptomatic 0.05, †† p = 0.01, ‡ p = 0.005 vs delayed RAS 2 mg/day. Repro-
benefits of treatment compared with baseline ap- duced from Siddiqui and Plosker[13] with permission.
peared to be more marked in patients with more at 6 months.[63] The beneficial effect of early- versus
pronounced symptoms at baseline (reported in a delayed-start rasagiline was maintained during the
poster).[66] Compared with placebo, rasagiline pro- long-term (6-year) follow-up period, suggesting that
duced improvements of >6 UPDRS units in patients early use of rasagiline may delay symptom progres-
with Parkinson’s disease of greater severity at base- sion.[63] A similar proportion of patients in the early-
line (baseline total UPDRS score >31) over a period and delayed-start treatment groups received
of 6 months.[66] levodopa and/or dopamine agonists (66% and 70%);
Health-related quality of life (HR-QOL), as mea- the median time from baseline to the addition of
sured by the PD-QUALIF scale,[67] stabilised with levodopa and/or dopamine agonists was similar in
rasagiline monotherapy versus placebo over the ini- each treatment group (1.5 and 1.8 years).[63]
tial 26-week study period; the between-group differ-
ence in the change from baseline in the PD-QUALIF 4.2 As Adjunctive Therapy in Patients with
score at 26 weeks with rasagiline 1 and 2 mg/day Moderate to Advanced Parkinson’s Disease
relative to placebo was –2.91 (95% CI –5.19, –0.64; and Motor Fluctuations
p = 0.01) and –2.74 (95% CI –5.02, –0.45; p =
0.02).[58,68] The duration of rasagiline treatment did The efficacy of once-daily rasagiline as an ad-
not affect HR-QOL; at the end of the 52-week junct to treatment with levodopa plus a dopa-de-
active-treatment phase, there were no differences carboxylase inhibitor (DDCI) in patients with motor
between early- and delayed-start rasagiline in the fluctuations was evaluated in the PRESTO (Parkin-
change from baseline in the PD-QUALIF score.[68] son’s Rasagiline: Efficacy and Safety in the Treat-
The improvement in HR-QOL in the entire study ment of ‘Off’)[60] and LARGO (Lasting effect in
group in the TEMPO trial was shown to be indepen- Adjunct therapy with Rasagiline Given Once-dai-
dent of age (age <65 years vs ≥65 years) in a post ly)[59] trials (table IV and table V). There were no
hoc analysis reported in a poster.[69] dietary tyramine restrictions in these trials. Patients
with moderate to advanced Parkinson’s disease (Ho-
Significantly more patients who received
ehn and Yahr stage <5 in the ‘off’ state) and
rasagiline 1 and 2 mg/day as monotherapy compared
levodopa-related motor fluctuations (shifts between
with placebo recipients responded to treatment (a
‘on’ and ‘off’ periods) were randomised to receive
<3-unit worsening in total UPDRS score) after 26
rasagiline 0.5 or 1 mg/day or placebo for 26 weeks
weeks (66% and 67% vs 49%; p ≤ 0.004).[58] The
in the PRESTO trial (n = 472)[60] or rasagiline 1 mg/
proportion of responders was also significantly
day, entacapone 200mg (with each levodopa dose)
higher following treatment with rasagiline 2 mg/day
or placebo for 18 weeks in the LARGO trial (n =
for 52 weeks compared with delayed-start rasagiline
687).[59] Patients had to be receiving an optimised
(64% vs 52%; p = 0.04).[61] There was no significant
regimen of levodopa at least three times daily (not
difference in the response rate between the
including a bedtime dose); the levodopa regimen[60]
rasagiline 1 mg/day and delayed-start rasagiline
or patients[59] had to be stable for at least 14 days
treatment groups at 52 weeks (53% vs 52%).
prior to baseline. Concomitant stable antiparkin-
In the long-term extension phase of 6.5 years, the sonian medication, including a dopamine agonist,
proportions of patients who were maintained on was permitted,[59,60] except for selegiline, enta-
rasagiline and did not require additional dopaminer- capone and tolcapone in the LARGO trial[59] and
gic therapy at 2 and 6 years were 45% (121 of 266 selegiline and tolcapone in the PRESTO trial.[60]
patients) and 17% (45 of 266).[62] Patients who had previously used entacapone were
Patients who received early-start rasagiline had a also excluded from the LARGO trial.[59]
16% smaller increase from baseline in total UPDRS The primary efficacy variable in both trials was
score (indicating less functional decline) compared the change from baseline in mean total daily ‘off’
with delayed-start rasagiline recipients (p = 0.006) time as measured by patients’ home diaries.[59,60]
Table IV. Efficacy of oral rasagiline (RAS) 0.5mg or 1mg once daily in conjunction with levodopa therapy in patients with moderate to advanced Parkinson’s disease.[59,74] Data
1736
shown are 18-[59,72] and 26-week[60,73] results in the intention-to-treat population in two randomised, double-blind, placebo-controlled, multicentre trials
Trial (no. of Comparison Between-group difference in the adjusted mean change from baseline (95% CI)a
patients) regimens total daily ‘off’ CGI scored,e UPDRS ADL UPDRS motor PD-QUALIF daily ‘on’ time daily ‘on’ time total daily ‘on’
time (h)b,c score during ‘off’ score during ‘on’ scorec,f without with time (h)c
timec,e timec,e dyskinesias (h)c dyskinesias (h)c
LARGO[59,72] RAS 1 mg/ –0.78*** –0.49*** –1.71*** –2.94*** 0.85 0.82** 0.09 0.86***
(n = 658) day vs PL (–1.18, –0.39) (–0.68, –0.31) (–2.49, –0.93) (–4.28, –1.60) (0.36, 1.27) (–0.28, 0.46) (0.47, 1.26)
ENT –0.80*** –0.36** –1.38** –2.73*** 0.85 0.82** 0.04 0.74**

200mgg vs (–1.20, –0.41) (–0.54, –0.17) (–2.16, –0.60) (–4.07, –1.39) (0.36, 1.27) (–0.32, 0.41) (0.34, 1.14)
PL
PRESTO[60,73] RAS 0.5 –0.49* –0.39* –1.20* –2.91** –2.18 0.51* –0.05 0.4
© 2007 Adis Data Information BV. All rights reserved.

(n = 450) mg/day vs (–0.91, –0.08) (–0.64, –0.13) (–2.08, –0.32) (–4.59, –1.23) (–4.49, 0.14) (0.00, 1.03) (–0.41, 0.31)h (–0.03, 0.82)
PL
RAS 1 mg/ –0.94** –0.68* –1.34** –2.87** –1.48 0.78** 0.37* 1.02***
day vs PL (–1.36, –0.51) (–0.94, –0.42) (–2.24, –0.43) (–4.58, –1.16) (–3.86, 0.90) (0.26, 1.31) (0.00, 0.74)h (0.59, 1.46)
a Results were adjusted using an analysis of covariance model that accounted for baseline mean total daily ‘off’ time,[59,60] treatment group[60] and centre.[60]
b Primary endpoint.
c At baseline, mean daily ‘off’ time was 6.0–6.3[60] and 5.6[59] hours; mean daily ‘on’ time with dyskinesias was 1.0–1.1[60] and 1.4[59] hours; mean daily ‘on’ time without
dyskinesias was 9.4–9.8[60] and 9.0–9.1[59] hours; mean UPDRS ADL score during ‘off’ time was 15.5–15.7[60] and 18.9–19.1;[59] and mean UPDRS motor score during ‘on’
time was 20.7–21.4[60] and 23.1–24.0.[59] Mean total daily ‘on’ time at baseline was 10.4–10.7[73] and 10.4–10.5[72] hours.
d A 7-point scale was used to assess the change from baseline in CGI score during the study period (–3 = markedly improved; –2 = moderately improved; –1 = minimally
improved; 0 = unchanged; 1 = minimally worse; 2 = moderately worse; 3 = markedly worse).[59] Baseline values were not reported.[59,60]
e Secondary endpoint.[59,60]
f Secondary endpoint (PRESTO study only).[60]
g Administered with every levodopa dose.[59]
h Analysis includes the treatment x centre interaction.
ADL = activities of daily living; CGI = Clinical Global Impression; PD-QUALIF = Parkinson’s Disease Quality of Life scale; UPDRS = Unified Parkinson’s Disease Rating Scale; * p ≤
0.05, ** p ≤ 0.005, *** p ≤ 0.0001 vs PL.
Drugs 2007; 67 (12)

Oldfield et al.
Table V. Efficacy of oral rasagiline (RAS) 1mg once daily with levodopa therapy in patients with moderate to advanced Parkinson’s disease.
Data shown are 18-week results of Unified Parkinson’s Disease Rating Scale (UPDRS) secondary analyses and assessments of ancillary
efficacy in the LARGO trial[59,72]
Comparison regimens Adjusted mean change from baseline in UPDRS scores
tremor rigidity bradykinesia

RAS 1mg/day (n = 231) –0.88* –0.70* –1.55***
ENT 200mga (n = 227) –0.81* –0.85** –1.44**

PL (n = 229) –0.28 –0.11 –0.19
a Administered with every levodopa dose.
ENT = entacapone; PL = placebo; * p < 0.01, ** p < 0.001, *** p < 0.0001 vs PL.
Secondary analyses, listed in a pre-specified order graphical locations, rasagiline 1 mg/day showed
used for the purposes of statistical analysis, included comparable efficacy and consistent treatment bene-
the Clinical Global Impression (CGI) score[59,60] and fits in patients with moderate to advanced Parkin-
the change from baseline in the UPDRS ADL score son’s disease in these two studies.[75]Adjunctive
during ‘off’ time,[59,60] the UPDRS motor score dur- therapy with rasagiline 0.5 or 1 mg/day significantly
ing ‘on’ time[59,60] and the PD-QUALIF score decreased the amount of daily ‘off’ time compared
(PRESTO trial only).[60] Statistical analysis was with placebo (between-group differences are shown
conducted on the ITT population, including all pain table IV).[59,60] Mean adjusted total daily ‘off’
tients with at least one post-randomisation measure- time was reduced from baseline by 1.18–1.85 hours
ment or diary entry for that endpoint.[59,60] For sec- with rasagiline 1 mg/day,[59,60] 1.41 hours with
ondary endpoints in the PRESTO study[60] and for rasagiline 0.5 mg/day,[60] by 1.20 hours with enta-
endpoints that were not derived from diaries in the capone[59] and by 0.40[59] and 0.91[60] hours with
LARGO study,[59] LOCF analysis was used where placebo.
data were missing or incomplete.
Compared with placebo, rasagiline significantly
Two ancillary studies conducted within the LAR- increased daily ‘on’ time without troublesome dys-
GO trial framework (available as posters and ab- kinesia, improved CGI scores and decreased
stracts) assessed the effect of rasagiline on freezing UPDRS ADL scores during ‘off’ time (table
of gait (n = 454; 10 weeks’ follow-up)[70] and severi- IV).[59,60] Rasagiline treatment did not affect HR-
ty of motor symptoms during ‘off’ time (n = 105; 18 QOL in the more advanced patients in the PRESTO
weeks’ follow-up).[71] Additional 18-week LARGO trial; the change from baseline in the PD-QUALIF
trial results[72] and 26-week PRESTO trial results[73] score with rasagiline 0.5 and 1 mg/day was not
have also been reported. significantly different from that observed with pla-
At baseline, mean daily ‘off’ time and mean daily cebo (table IV).[60] In the LARGO trial, entacapone
levodopa dosage were similar across treatment arms also significantly improved daily ‘off’ time, daily
in both trials.[59,60] Patients in the LARGO trial had ‘on’ time without dyskinesia and UPDRS ADL
5.55–5.60 hours of mean daily ‘off’ time and were scores relative to placebo (table IV).[59]
receiving levodopa 697–722 mg/day at baseline.[59] Rasagiline also significantly improved motor
In the PRESTO trial, patients had 6.0–6.3 hours of symptoms during both ‘on’ and ‘off’ time;[59,60,71]
mean daily ‘off’ time and were receiving levodopa the change from baseline in UPDRS motor scores
750–821 mg/day at baseline.[60] during ‘on’ and ‘off’ time significantly favoured
Rasagiline significantly improved motor fluctua- rasagiline compared with placebo.[59,60,71] The
tions in patients with moderate to advanced Parkin- change in UPDRS motor score during ‘on’ time was
son’s disease already optimised on levodopa and significantly greater with rasagiline and entacapone
other therapies.[59,60] Although the PRESTO and compared with placebo (table IV).[59,60] The UPDRS
LARGO trials were conducted in different geo- motor score during ‘off’ time was 5.64 units lower
with rasagiline than placebo in a substudy of LAR- concomitant use of dopamine agonists. Rasagiline
GO (p = 0.013); the effect of entacapone was not and entacapone recipients in this study also had a
significant versus placebo in this substudy.[71,76] significant reduction in levodopa dosage (–24 and
–19 mg/day vs +5 mg/day with placebo; p = 0.0003)

Levodopa-responsive symptoms, including trem-
[the levodopa dosage could be adjusted only during
or, rigidity and bradykinesia, improved with

rasagiline according to post hoc analysis in the the first 6 weeks of the LARGO trial].[59]
LARGO trial[59] and a pre-specified analysis in an Improvements in motor function with rasagiline
ancillary study to the LARGO trial.[70] Compared were similar in patients already optimised on
with placebo, significant improvements in UPDRS levodopa and other concomitant Parkinson’s disease
tremor, rigidity and bradykinesia subscores were therapy and patients who were not receiving con-
reported with rasagiline and entacapone[59] (table comitant therapy, according to subgroup analyses of
V).[72] Tremor, rigidity and bradykinesia also im- the LARGO[77] and PRESTO[78] trials. Entacapone
proved in the PRESTO trial.[60] Within the LARGO recipients in the LARGO trial also experienced im-
trial, the change from baseline in the UPDRS freez- provements in motor function either with or without
ing subscale score for patients who displayed freez- concomitant dopamine agonist therapy, with the ex-
ing when walking at baseline (n = 278) significantly ception of changes in CGI and UPDRS ADL scores
favoured rasagiline 1 mg/day versus placebo recipi- during ‘off’ time, which were similar to those in
ents (between-group difference –0.16; p = 0.045).[59] placebo recipients.[77]
In addition, compared with placebo, the UPDRS As a large proportion of patients with Parkin-
postural instability gait difficulty subscore was sig- son’s disease are elderly, pooled data from the sub-
nificantly improved in recipients of rasagiline 1 mg/ group of patients aged ≥70 years who participated in
day (between-group difference = –0.31; p = 0.034) the PRESTO and LARGO trials were analysed to
but was not improved in entacapone recipients.[59] In assess treatment efficacy in these patients compared
an ancillary study of the LARGO trial, patients who with that in younger patients.[79] Adjunctive
received rasagiline 1 mg/day (n = 150) for 10 weeks rasagiline treatment 1 mg/day was shown to be
experienced a significantly greater decrease from effective in patients in this older patient population
baseline in the score for the Freezing of Gait Ques-
with the efficacy of the drug unaffected by the age of
tionnaire compared with placebo recipients (n = the patient.[79] Another analysis of pooled data from
154) [–1.17 vs –0.48; p = 0.045].[70] The changes the PRESTO and LARGO studies showed that high-
from baseline in the UPDRS tremor, rigidity and level responses to adjunctive rasagiline therapy 1
bradykinesia subscale scores at 18 weeks in the mg/day were achieved in levodopa-treated patients
LARGO trial also significantly favoured rasagiline with varying degrees of disease severity at baseline,
1 mg/day as well as entacapone versus placebo with no between-group differences in responses evi-
recipients; between-group differences for rasagiline dent.[80] High-level responses were defined as the
versus placebo were –0.6, –0.6 and –1.36, respec- highest quartile of responders in each group (reduc-
tively (p ≤ 0.0065 for each comparison).[59] tion in ‘off’ time of >2.56 hours or a >46% reduction
Response to treatment, defined as a ≥1-hour de- in ‘off’ time).[80] Moreover, patients with Parkin-
crease in mean total daily ‘off’ time, was significant- son’s disease of moderate severity (as defined by
ly greater with rasagiline than placebo in the LAR- two criteria: on levodopa only, mild fluctuations)
GO trial; 113 of 222 (51%) patients in the rasagiline with motor fluctuations at baseline were shown to
treatment group were responders compared with 70 have reductions in daily ‘off’ time and improve-
of 218 (32%) in the placebo group (p < 0.0001).[59] ments in various global measures after treatment
In the entacapone group, 99 of 218 (45%) patients with adjunctive rasagiline 1 mg/day in a post hoc
were responders (p = 0.0019 vs placebo). The re- analysis of data from the PRESTO and LARGO
sponse to treatment was not affected by age or studies.[81]
5. Tolerability <1%), sleep disorder (6% vs 4%), somnolence (3%

vs <1%), ataxia (3% vs <1%) and flatulence (3% vs
Rasagiline tolerability was assessed during 0%).[91] During the TEMPO trial follow-up period,
clinical trials of oral rasagiline 1 or 2 mg/day as the most common adverse events reported with
monotherapy in patients with early Parkinson’s dis- rasagiline were infection, accidental injury, nausea
ease (the TEMPO trial)[58,61,62] and rasagiline 0.5 or and arthralgia.[62]

1 mg/day in conjunction with levodopa in patients
Rasagiline 0.5 or 1 mg/day was generally well
with moderate to advanced disease (the PRESTO
tolerated when administered in conjunction with
and LARGO trials)[59,60] [see sections 4.1 and 4.2 for
trial details]. Additional tolerability data were ob- levodopa plus a DDCI and other antiparkinsonian
tained from retrospective analyses of data from the medication for up to 26 weeks in patients with
studies and other reports, some of which are ab- moderate to advanced disease and motor fluctua-
stracts and posters.[74,79,82-90] tions; the most commonly occurring adverse events
Rasagiline 1 or 2 mg/day monotherapy was gen- were dopaminergic related.[59,60] In the PRESTO and
erally well tolerated in patients with early Parkin- LARGO trials, treatment discontinuation rates were
son’s disease,[58,61,74] regardless of age.[79,82] The low (4.2% with rasagiline vs 4.9% with placebo).[83]
most commonly occurring adverse events in recipi- The most common cognitive and behavioural ad-
ents of rasagiline monotherapy during the first 26 verse events in rasagiline 1 mg/day and placebo
weeks of the TEMPO trial were infection, headache recipients were sleep disorders (8.1% vs 6.9%),
and arthralgia (figure 2).[58] The most common cog- somnolence (6% vs 4.4%), depression (4.7% vs
nitive and behavioural adverse events in rasagiline 1 6.3%), hallucinations (4% vs 3.1%) and confusion
mg/day and placebo recipients were sleep disorders (1.3% vs 0.6%).[74] The incidence of dopaminergic
(3.7% vs 4.3%), somnolence (0% vs 1.4%), depres- adverse events with rasagiline and placebo plus
sion (5.2% vs 2.2%) and hallucinations (0.7% vs levodopa in the LARGO trial is depicted in figure
0.7%).[74] There was a numerically higher incidence 3.[59] In the PRESTO trial, rasagiline 1 mg/day re-
of dopaminergic adverse events with rasagiline 2 cipients reported a significantly greater incidence of
mg/day than with rasagiline 1 mg/day, including weight loss (9.4% vs 2.5%), vomiting (6.7% vs
abnormal dreams (3% vs 0.7%), vomiting (3% vs 1.3%) and anorexia (5.4% vs 0.6%) than placebo
18 RAS 1 mg/day
RAS 2 mg/day
16 PL
14
12
Patients (%)
10
6
* *
4
0
Accidental Arthralgia Asthenia Back pain Dizziness Headache Infection Nausea Pain
injury
Fig. 2. Tolerability profile of oral rasagiline (RAS) monotherapy in patients with early Parkinson’s disease not receiving levodopa. The
incidence of non-cognitive adverse events that occurred with a frequency of >5% in any treatment arm in 404 patients who received RAS
1 mg/day or 2 mg/day or placebo (PL) for 26 weeks in the randomised, double-blind TEMPO trial is depicted.[58] * p = 0.05 vs PL.
7 RAS (n = 231)
ENT (n = 227)
6 PL (n = 229)
5
Patients (%)
4
1
ø ø ø ø ø ø
0
io l
th
ng
on
ss
ns
er
e
ns ra
et
op
io
oe
se
io
si
nc
ou
rd
ne
tio
te tu
iti
si
n
ne
at
ea
xi
ss
de
au
le
nc
rrh
so
m
fu
po os
An
zi
na
ip
re
ki
no
dr
oe
Vo
on
Sy
iz
di
ia
hy P
st
ry
ys
ep
ci
m
D
al
D
on
C
l
p
D
lu
ra
D
D
So
rm
ee
al
C
he
Sl
no
rip
Ab
Pe
Fig. 3. Dopaminergic adverse event profile of oral rasagiline (RAS) in conjunction with levodopa plus a peripheral dopa-decarboxylase
inhibitor in patients with moderate to advanced Parkinson’s disease. In the double-blind LARGO trial, 687 patients with motor fluctuations
were randomised to receive RAS 1 mg/day, entacapone (ENT) 200mg with each levodopa dose or placebo (PL) for 18 weeks.[59] ø indicates
incidence of <1%.
recipients (p ≤ 0.04 for each comparison).[60] In the Rasagiline was generally associated with low
same trial, patients who received rasagiline 0.5 mg/ discontinuation rates due to adverse events when
day had a significantly greater incidence of balance administered as monotherapy[62] or as adjunctive
difficulty than placebo recipients (5.5% vs 0.6%; p = therapy.[59] Over 6.5 years, 45 of 398 (11.3%) of
0.03), and rasagiline recipients (both dosages com- patients withdrew from the TEMPO trial because of
bined) experienced a significantly greater incidence adverse events.[62]
of dyskinesias compared with placebo (18% vs Serious adverse events with rasagiline were also
10%; p = 0.03).[60] Depression occurred significant- infrequent, occurring in 5–12% of rasagiline 0.5–2
ly less frequently with rasagiline 0.5 mg/day than mg/day recipients and in 3–9% of placebo recipients
placebo in the PRESTO trial (p = 0.04; percentage in all three trials.[58-60] The most common serious
of patients not reported).[60] adverse events occurring in any treatment group
Rasagiline was generally well tolerated by elder- (including placebo) in the PRESTO trial were relat-
ly (aged ≥70 years) patients when administered as ed to accidental injury (n = 6), arthritis, worsening
monotherapy[82] or in conjunction with lev- Parkinson’s disease, melanoma, stroke and urinary
odopa.[59,79,82] Regardless of treatment with tract infection (n = 3 each).[60] Data from a clinical
rasagiline or placebo, elderly (aged ≥70 years) pa- screening programme that was implemented in
tients experienced a significantly higher incidence ongoing trials following the occurrence of some
of serious adverse events in the TEMPO and PRES- cases of melanoma suggest that Parkinson’s disease
TO trials (p ≤ 0.04), symptomatic orthostatic hypo- patients have an increased risk for melanoma.[91]
tension in the TEMPO trial (p = 0.01) and hallucina- Epidemiological studies have also indicated that
tions in the PRESTO trial (p = 0.01) than patients there is a higher incidence of Parkinson’s disease
aged <70 years.[82] Patients aged <70 and ≥70 years among patients with melanoma than the general
reported similar incidences of total adverse events, population.[92-97]
dyskinesias and confusion in the PRESTO and Rasagiline treatment had no clinical effect on
TEMPO trials[82] and dopaminergic adverse events ECG recordings, blood pressure, heart rate or labo-
in the LARGO trial.[59] ratory measurements.[58-60,84] In the PRESTO trial, a
greater number of patients receiving rasagiline 0.5 There was no evidence of unexpected adverse
mg/day than placebo had low standing systolic (20 events or serotonin toxicity in the records of 316
vs 8mm Hg) or diastolic (9 vs 1mm Hg) blood pres- patients with Parkinson’s disease who received
sure (p < 0.05); no differences were observed be- rasagiline (dosage range 0.5 to 10 mg/day) and
tween the rasagiline 1 mg/day and placebo treatment concomitant antidepressants (e.g. tricyclics, selec-
groups.[60] tive serotonin reuptake inhibitors [SSRIs]) [median

treatment time 316 days] in several controlled
No increase in sensitivity to tyramine was ob-
clinical trials in a retrospective analysis.[89] Moreo-
served in six healthy adult volunteers who received
ver, there was no increase in the rate of study
rasagiline 1 mg/day for 10 days.[85] Furthermore,
termination due to adverse events in this group of
sensitivity to tyramine increased only slightly in six
patients.[89] In addition, no deleterious clinical inter-
volunteers who received rasagiline 2 mg/day for 10
actions between rasagiline and SSRIs were identi-
days; this change in sensitivity to tyramine was fied among 77 patients in the PRESTO trial, accord-
similar to that seen with selegiline 10 mg/day.[85] ing to preliminary results of a safety substudy.[90]
Rasagiline did not interact with tyramine in sub- Although the patients receiving concomitant SSRIs
studies of the TEMPO[86,87] and PRESTO[87,88] trials. experienced a numerically higher incidence of
A single dose of 50[88] or 75mg[86] of tyramine vomiting than patients who did not receive SSRIs
hydrochloride was administered to 55 patients on (5% vs 1%; p-value not reported), there were no
the last day of the placebo-controlled phase of the other notable between-group differences in the inci-
TEMPO trial[86,87] and 55 patients who completed dence of adverse events.[90]
the PRESTO trial.[87,88] None of the patients in the
TEMPO substudy experienced a tyramine reaction
(defined as an increase in systolic blood pressure of 6. Dosage and Administration
>30mm Hg sustained for ≥10 minutes, bradycardia
[heart rate <40 beats per minute] or significant ECG Rasagiline 1mg tablets are approved in Europe
changes).[86,87] Four of the patients in the PRESTO for use in the treatment of idiopathic Parkinson’s
substudy had increases in systolic blood pressure disease as initial monotherapy or as an adjunct to
of≥30 mmHg for 10 minutes on three consecutive levodopa in patients with end-of-dose motor fluctu-
measurements;[88] three patients had received ations.[11] The recommended dosage is 1mg once
rasagiline 0.5 mg/day (none had received rasagiline daily with or without levodopa in adults aged ≥18
1 mg/day) and one patient had received placebo.[88] years. In the US, the recommended dosage of
The pattern of systolic blood pressure elevation in rasagiline monotherapy is 1mg once daily.[12] As
two of the three rasagiline patients was atypical for a adjunctive therapy, the recommended initial dosage
tyramine response and none of the four patients is 0.5mg once daily; the dose may be increased to
demonstrated clinically significant ECG changes, 1mg once daily if a sufficient clinical response is not
reflex bradycardia or adverse symptoms associated achieved.[12]
with a tyramine response.[88] Accordingly, the study Because of the route of metabolism (section 3.2),
investigators reported that rasagiline 1 mg/day can rasagiline is contraindicated in patients with severe
be taken with or without food and no dietary tyra- hepatic insufficiency, and should be avoided in pa-
mine restrictions are needed.[84,87] Of note, all three tients with moderate hepatic impairment.[11] Accord-
phase III trials were conducted without dietary tyra- ing to the US prescribing information,[12] the dosage
mine restriction[85] and no cases of hypertensive of rasagiline for patients with mild hepatic impair-
crisis were reported. Measurements of blood pres- ment is 0.5mg once daily; patients with moderate or
sure taken before and after the main meal showed no severe hepatic impairment should not be treated
significant between-group differences in the PRES- with rasagiline.[12] Local prescribing information
TO trial.[60] should be consulted for information about other
contraindications, precautions and recommended disease and surgery and rehabilitation are also op-
dosages for special populations. tions for treatment, although the efficacy of these
There are several known interactions between interventions is still being investigated.[98] The pri-
nonselective MAO inhibitors and other drugs.[11] mary goals of treatment for all patients, regardless of
Consequently, the following recommendations ap- the severity of their symptoms, are to target the most
ply to the use of rasagiline, according to the Europe- disabling symptoms and, if possible, to slow the
an prescribing information.[11] The concomitant use progression of the disease.[99]
of rasagiline and other MAO inhibitors or pethidine Although patients at all stages of the disease
is contraindicated. In addition, the concomitant use usually experience clinically meaningful benefit
of rasagiline and dextromethorphan or sympath- from levodopa treatment,[2,7,9] over time the quality
omimetics (e.g. decongestants containing ephedrine of the therapeutic response to levodopa deteriorates
or pseudoephedrine) is not recommended, and an- and patients develop disabling motor fluctuations
tidepressants (e.g. SSRIs, tricyclic/tetracyclic an- (including the ‘wearing-off’ effect and the ‘on-off’
tidepressants, MAO inhibitors) or potent CYP1A2 phenomenon), dyskinesias, confusion and hallucina-
inhibitors (e.g. ciprofloxacin; see also section 3.2) tions.[9,98] After 5 years of levodopa treatment,
should be administered with rasagiline with caution. 25–50% of patients experience motor fluctuations;
In addition, the use of fluoxetine or fluvoxamine in young-onset patients the prevalence increases to
with rasagiline should be avoided.[11] In the US >90%.[2]
prescribing information[12] it is recommended that Therefore, the decision about when to initiate
the dosage of rasagiline should be reduced to 0.5mg levodopa therapy involves consideration of the need
once daily in patients receiving concomitant for rapid symptomatic relief versus the possibility of
ciprofloxacin or other CYP1A2 inhibitors. delaying levodopa treatment to postpone the devel-
opment of motor complications and other debilitat-
7. Place of Rasagiline in the ing levodopa-related effects.[98] Treatment with oth-
Management of Parkinson’s Disease er agents, such as MAO-inhibitors or dopamine
agonists, may be initiated as part of a levodopa-
Parkinson’s disease is a neurodegenerative dis-
sparing strategy.[2,7,9]
ease that occurs commonly in most countries world-
wide.[1] It is increasingly common in the elderly, and In patients with more advanced disease who ex-
studies have shown that it is slightly more prevalent perience levodopa-related motor fluctuations,
in men than in women.[1] Young-onset Parkinson’s dopamine agonists or COMT inhibitors may be ad-
disease occurs in people aged <40 years and ac- ded to levodopa treatment to reduce ‘off’ time.[2,98]
counts for approximately 5% of patients with the The patient’s daily dosing regimen becomes more
disease.[1] complex with the adjunctive use of these agents,
Treatment of Parkinson’s disease is complex be- many of which are administered at least twice daily
cause of the progressive nature of the disease; wors- and require individual dosage titration or adjustment
ening parkinsonian symptoms eventually necessitate of the levodopa dosage.[9] Although selegiline is
treatment initiation. The choice of therapy is in- also indicated for use in conjunction with levodopa,
dividualised according to the degree of functional various evidence-based treatment reviews have con-
disability that the patient experiences as a result of cluded that there is insufficient evidence to recom-
the disease.[9] Patient age and the tolerability of mend it for the purpose of alleviating levodopa-
current medication should also be considered before related motor complications.[98,100,101]
selecting an appropriate treatment. There is a grow- In the EU and the US, rasagiline is indicated as
ing trend to treat Parkinson’s disease at an early monotherapy or in conjunction with levodopa in
stage.[8] A wide range of pharmacological treatment patients with Parkinson’s disease (section 6).[11,12] In
options are available for use at different stages of the randomised clinical trials, rasagiline monotherapy
had a significant effect on Parkinson’s symptoma- patients still in the study were adequately controlled
tology in patients with early Parkinson’s disease by rasagiline monotherapy and did not require addi-
compared with placebo (section 4.1)[58,61] and this tional dopaminergic therapy (section 4.1).[62] Of
benefit was maintained in the long term thereby note, a large, randomised, double-blind study, the
establishing it as a useful option for initial sympto- ADAGIO (Attenuation of Disease Progression with
matic monotherapy as part of a levodopa-sparing Rasagiline Once-Daily) study is currently underway

treatment strategy. Recent evidence-based reviews with the aim of determining whether rasagiline has
recommend rasagiline as efficacious monotherapy potential disease modifying effects in patients with
for the control of symptoms of Parkinson’s dis- very early Parkinson’s disease.[105]
ease[102] or as a treatment to reduce ‘off’ time in Rasagiline is also indicated for use as an adjunct
patients with Parkinson’s disease with motor fluctu- to levodopa and has demonstrated efficacy in this
ations and dyskinesia.[103] In addition, clinical evi- indication in patients with moderate to advanced
dence supports the efficacy of MAO-B inhibitors in Parkinson’s disease in the PRESTO and LARGO
improving motor symptoms and daily living activi- trials (section 4.2). Results from the LARGO trial
ties, and in delaying the need for levodopa therapy, show that rasagiline and entacapone were signifi-
according to guidelines from the National Institute cantly favoured over placebo in terms of daily ‘off’
for Health and Clinical Excellence.[104] time, daily ‘on’ time without dyskinesia, UPDRS
No trials have been conducted to compare the ADL score during ‘off’ time and UPDRS motor
therapeutic efficacy of rasagiline with other agents score during ‘on’ time.[59] Furthermore, the UPDRS
indicated for use as monotherapy in patients with motor score during ‘off’ time was significantly low-
early Parkinson’s disease. However, the favourable er with rasagiline than with placebo in a LARGO
tolerability profile of rasagiline when given as substudy, whereas the effect of entacapone was not
monotherapy may offer an advantage over both significant versus placebo in this substudy.[71,76] In a
selegiline and dopamine agonists. Rasagiline was comparison of results from well designed clinical
well tolerated for up to 6.5 years during the TEMPO trials in patients with advanced Parkinson’s disease
extension trial.[58,61-63] Notably, rasagiline did not and motor fluctuations, the reduction in mean daily
increase the incidence of somnolence, hallucinations ‘off’ with rasagiline (1.9 hours) was similar to that
or confusion (adverse effects that occur frequently observed with pramipexole, ropinirole and enta-
with selegiline and dopamine agonists) when ad- capone (1.2–1.9 hours) although cross-trial compar-
ministered at the approved 1 mg/day dose (section isons should be made with caution.[74] Importantly,
5). Unlike selegiline, rasagiline is not metabolised to rasagiline improves the incidence of freezing of gait
amphetamine or amphetamine derivatives (section (section 4.2), a symptom which develops in most
3.2), and is therefore devoid of sympathomimetic patients as the disease progresses and is not relieved
activity.[38,55] by treatment with levodopa, dopamine agonists or
COMT inhibitors.[9,103]
Neuroprotective effects of rasagiline have been
observed in vitro and in animal studies (section 2.2). Rasagiline was generally well tolerated as ad-
Further investigation in the clinical setting is needed junctive therapy when administered at the approved
to determine whether this activity is borne out in dose in patients with moderate to advanced disease.
patients with Parkinson’s disease. Long-term data Although some dopaminergic effects, including
from the TEMPO and TEMPO extension studies dyskinesias, balance difficulty, weight loss, vomit-
demonstrating that early-start rasagiline patients ing and anorexia, occurred more frequently with
achieved a better degree of symptom control than rasagiline 0.5–1 mg/day than with placebo in the
delayed-start rasagiline patients suggest that PRESTO trial,[60] there was no difference in the
rasagiline may confer a disease-modifying effect incidence of these adverse events between rasagiline
(section 4.1).[63] After 2 years, almost half of the 1 mg/day and placebo treatment groups in the LAR-
GO trial (section 5).[59] Importantly, when adminis- 5. Mandel S, Grunblatt E, Riederer P, et al. Neuroprotective strate-
gies in Parkinson’s disease: an update on progress. CNS Drugs
tered at the approved dosage, rasagiline does not 2003; 17 (10): 729-62
potentiate cognitive and behavioural dopaminergic 6. Waldmeier PC. Prospects for antiapoptotic drug therapy of
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adverse effects such as hallucinations, confusion, ol Psychiatry 2003; 27 (2): 303-21
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preferable to other treatments in older patients, who best approach to treatment? Drugs Aging 2000; 17 (3): 165-81
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In conclusion, rasagiline, administered once dai- 14. Youdim MBH, Gross A, Finberg JPM. Rasagiline [N-
ly with no titration, is effective as initial monother- propargyl-1R(+)-aminoindan], a selective and potent inhibitor
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apy in patients with early Parkinson’s disease and as 132 (2): 500-6
adjunctive therapy in patients with moderate to ad- 15. Freedman NM, Mishani E, Krausz Y, et al. In vivo measurement
vanced disease and motor fluctuations. Rasagiline of brain monoamine oxidase B occupancy by rasagiline, using
11C-L-deprenyl and PET. J Nucl Med 2005 Oct; 46 (10):
has a favourable efficacy and tolerability profile 1618-24
when administered at the approved dose. Thus, 16. Rabey JM, Sagi I, Huberman M, et al. Rasagiline mesylate, a
rasagiline, administered as a simple and convenient new MAO-B inhibitor for the treatment of Parkinson’s disease:
a double-blind study as adjunctive therapy to levodopa. Clin
once-daily dosage regimen, is a well tolerated and Neuropharmacol 2000; 23 (6): 324-30
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18. Kupsch A, Sautter J, Gotz ME, et al. Monoamine oxidase-
Disclosure inhibition and MPTP-induced neurotoxicity in the non-human
primate: comparison of rasagiline (TVP 1012) with selegiline.
J Neural Transm 2001; 108 (8-9): 985-1009
During the peer review process, the manufacturer of the 19. Finberg JPM, Wang J, Bankiewicz K, et al. Increased striatal
agent under review was offered an opportunity to comment dopamine production from L-DOPA following selective inhi-
on this article; changes based on any comments received were bition of monoamine oxidase B by R(+)-N-propargyl-1-ami-
made on the basis of scientific and editorial merit. noindan (rasagiline) in the monkey. J Neural Transm 1998; 52
Suppl.: 279-85
20. Finberg JP, Youdim MB. Modification of blood pressure and
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Title: Rasagiline: A Review of its Use in the Management of Parkinson's Disease

Author(s): Oldfield, Vicki; Keating, Gillian M.; Perry, Caroline M.

Copyright Terms: . Storage for future similar use allowed

© 2007 Adis Data Information BV. All rights reserved.

A Review of its Use in the Management of

Various sections of the manuscript reviewed by:

Results of well designed clinical studies indicate that rasagiline is effective as

versus delayed-start (by 6 months) rasagiline 2 mg/day at 52 weeks. At 26 weeks,

tremor and bradykinesia scores also significantly favoured rasagiline recipients,

1. Introduction dysfunction and dementia, develop as the disease

Table I. Overview of the pharmacodynamic properties of rasagiline

Antiparkinsonian and motor restoration effects

14 nmol/L, compared with 710 nmol/L for inhibi-

for inhibition of MAO-B and MAO-A by selegiline

impairment on rasagiline pharmacokinetics is dis-

Three large (n > 400 per study) randomised,

a 26 weeks RAS 1 mg/day

adjusted UPDRS scores relative to placebo (95%CI)

Differences in change from baseline in mean

score indicates an improvement of symptoms). Both

confirmed that significantly less disease progression *

motor and ADL scores with rasagiline 1 and 2 mg/ b 52 weeks

day indicated that worsening of symptoms was sig- 1

and changes from baseline are shown in table III (p

for each comparison).[58] The between-group differ- ††

ed tremor score at 26 weeks was –0.63 (95% CI

ENT –0.80*** –0.36** –1.38** –2.73*** 0.85 0.82** 0.04 0.74**

© 2007 Adis Data Information BV. All rights reserved.

f Secondary endpoint (PRESTO study only).[60]

g Administered with every levodopa dose.[59]

h Analysis includes the treatment x centre interaction.

Drugs 2007; 67 (12)

tremor rigidity bradykinesia

ENT 200mga (n = 227) –0.81* –0.85** –1.44**

–19 mg/day vs +5 mg/day with placebo; p = 0.0003)

or, rigidity and bradykinesia, improved with

5. Tolerability <1%), sleep disorder (6% vs 4%), somnolence (3%

ease (the TEMPO trial)[58,61,62] and rasagiline 0.5 or and arthralgia.[62]

groups.[60] tive serotonin reuptake inhibitors [SSRIs]) [median

matic monotherapy as part of a levodopa-sparing Rasagiline Once-Daily) study is currently underway

neurodegenerative diseases. Prog Neuro-Psychopharmacol Bi-

w.emc.medicines.org.uk/emc/assets/c/html/displaydo- 72. Teva Pharmaceutical Industries Ltd. TVP-1012/Rasagiline

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ENT –0.80* –0.36 –1.38 –2.73* 0.85 0.82 0.04 0.74

ENT 200mga (n = 227) –0.81* –0.85 –1.44