Drugs

, Volume 72, Issue 5, pp 643–669 | Cite as

Rasagiline

A Review of its Use in the Treatment of Idiopathic Parkinson’s Disease
Adis Drug Evaluation

Abstract

Rasagiline (Azilect®), a selective, irreversible, monoamine oxidase-B inhibitor, is available in the EU, the US and in several other countries worldwide, including Canada and Israel. It is indicated for the treatment of idiopathic Parkinson’s disease as monotherapy or as adjunctive therapy to levodopa in patients with end-of-dose fluctuations in the EU and for the treatment of adult patients with the signs and symptoms of idiopathic Parkinson’s disease in the US. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of rasagiline as monotherapy or as adjunctive therapy to levodopa in patients with Parkinson’s disease.

Oral rasagiline as monotherapy or as adjunctive therapy to levodopa was effective in the symptomatic treatment of adult patients with Parkinson’s disease participating in double-blind, placebo-controlled, multinational studies. In patients with early Parkinson’s disease, monotherapy with rasagiline 1 mg/day (recommended dosage) significantly slowed the rate of worsening (i.e. an increase in the Unified Parkinson’s Disease Rating Scale [UPDRS] score) in the ADAGIO and TEMPO studies, with the results from the ADAGIO study for rasagiline 1 mg/day suggesting a slowing of clinical progression. However, at the higher dosage of 2 mg/day, rasagiline met the primary endpoint in the TEMPO study and the first, but not the second, of three hierarchical primary endpoints in the ADAGIO study. Compared with delayed-start rasagiline monotherapy, early initiation was associated with a slower long-term progression of the clinical signs and symptoms of Parkinson’s disease in the TEMPO study. As adjunctive therapy to levodopa in the LARGO and PRESTO studies, rasagiline 0.5 and/or 1 mg/day significantly reduced the total daily ‘off’ time (primary efficacy endpoint) and significantly improved the Clinical Global Impression score, the UPDRS activities of daily living subscale score during ‘off’ time and the UPDRS motor subscale score during ‘on’ time compared with placebo in patients with advanced Parkinson’s disease.

Although rasagiline showed neuroprotective properties both in vitro and in vivo, identifying its potential to slow clinical progression in the clinical setting has been elusive to date and was not definitively demonstrated in the studies discussed in this article. Additional rasagiline studies specifically designed to assess the clinical progression of Parkinson’s disease while addressing the potentially confounding factors of the delayed-start study design would therefore be of interest.

As monotherapy or as adjunctive therapy to levodopa, rasagiline was generally well tolerated, with the frequency and nature of treatment-emergent adverse events generally similar across clinical studies and between rasagiline and placebo groups. Therapy with rasagiline appears to be associated with a low incidence of cognitive and behavioural adverse events.

Thus, oral rasagiline as monotherapy or as adjunctive therapy to levodopa provides a useful option in the treatment of adult patients with Parkinson’s disease.

1. Introduction

Parkinson’s disease is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta and the appearance of intracellular inclusions (Lewy bodies).[1,2] It is the loss of these dopaminergic neurons that results in the motor impairments (i.e. bradykinesia [slowness of movement], muscular rigidity, postural instability and resting tremor) observed with Parkinson’s disease.[2,3] Non-motor symptoms are also frequently observed and include autonomic disturbances (e.g. bladder and bowel dysfunction, postural hypotension), falls, mental health issues (e.g. anxiety, apathy, dementia, depression, psychosis), pain and sleep disturbances (e.g. hypersomnolence, nocturnal akinesia, restless legs syndrome).[4]

The majority of pharmacological therapies utilized for the management of Parkinson’s disease focus on restoring striatal dopamine.[1,5] This can be accomplished by increasing the supply of dopamine (e.g. with the prodrug dopamine precursor levodopa), directly stimulating post-synaptic dopamine receptors (with dopamine agents), impeding dopamine metabolism or inhibiting dopamine reuptake.[1,3] However, therapies utilizing other mechanisms of action are also available.[5]

Monoamine oxidase (MAO) is a protein of the outer mitochondrial membrane.[6] It metabolizes neurotransmitters in the brain and other tissues and protects against the destructive effects of dietary amines; its inhibition potentially elevates the levels of its neurotransmitter substrates (e.g. dopamine, tyramine).[6] MAO is classified as type A (MAO-A) or type B (MAO-B); MAO-A is found primarily in the intestinal tract (but is also present in the presynaptic neurons of the brain), whereas MAO-B is predominately found in the brain (principally localized to glial cells bordering dopaminergic synapses) and regulates both the releasable stores and free intraneuronal levels of dopamine.[5,7] Given the role of MAO-B in the metabolism of dopamine, selective MAO-B inhibitors are a therapeutic option for patients with Parkinson’s disease.[6]

This article reviews the pharmacological properties, therapeutic efficacy and tolerability of rasagiline (Azilect®), a selective, irreversible MAO-B inhibitor, as monotherapy or as adjunctive therapy to levodopa in patients with Parkinson’s disease.

2. Pharmacodynamic Properties

The pharmacodynamic properties of oral rasagiline are well established and have been reviewed previously;[8,9] therefore, a brief overview is presented in the following section.

Rasagiline is a selective, irreversible MAO-B inhibitor, with such activity believed to increase striatal extracellular dopamine levels.[10,11]

As reviewed by Oldfield et al.,[9] the selective and irreversible MAO-B inhibitory activity of rasagiline has been demonstrated in a number of in vitro and in vivo studies; moreover, in a rat model, it was shown to be up to 5-fold more potent than selegiline in inhibiting MAO-B activity following repeated administration.[12] In healthy volunteers (n = 12) who received a single dose of oral rasagiline 1, 2, 5 or 10 mg, maximal inhibition (by approximately 35%, 55%, 79% and 99%, respectively; all p < 0.05 vs placebo) of platelet MAO-B activity (a marker for brain MAO-B activity) was observed 1 hour post-dose.[13] The observed inhibition was dose dependent and maintained for at least 48 hours post-dose, with platelet MAO-B activity returning to baseline values 2 weeks post-dose.[13]

The inhibition of platelet MAO-B activity was also demonstrated following the oral administration of multiple doses of rasagiline.[13] In healthy volunteers (n = 24), significant (p < 0.05) between-group differences in platelet MAO-B inhibition favouring rasagiline 2, 5 and 10 mg/day over placebo were evident 2 hours following the first dose, with multiple doses of rasagiline 2 mg/day resulting in almost complete (>99%) MAO-B inhibition on day 6.[13] The time to maximal inhibition was reduced in a dose-dependent manner; moreover, according to a regression analysis, the percentage of platelet MAO-B inhibition correlated with the log of the maximum plasma rasagiline concentration (Cmax) [correlation coefficient 0.79; p < 0.001].[13] For all multiple doses, maximal inhibition was maintained until 24 hours after the last dose, with platelet MAO-B activity returning to baseline levels 2 weeks post-dose.[13] Platelet MAO-B activity was also completely inhibited after 1 week of rasagiline 0.5, 1 or 2 mg/day in patients with Parkinson’s disease.[14]

These data are supported by a smaller (n = 3) study in healthy volunteers[15] who received rasagiline 1 mg/day for 10 days. Neuroimaging utilizing 11C-deprenyl positron emission tomography revealed the specific binding of rasagiline to MAO-B, resulting in a reduction in MAO-B binding in the thalamus and basal ganglia. A recovery in MAO-B binding in these areas occurred gradually over the following 6 weeks, consistent with the reported half-life (t1/2) for the de novo synthesis of MAO-B in the human brain (40 days).[15]

A recent study[16] in healthy volunteers designed to determine the MAO-B selectivity and tyramine sensitivity (via blood pressure [BP] measurements) of rasagiline found rasagiline 1 mg/day to be selective for MAO-B inhibition (i.e. not associated with clinically significant MAO-A inhibition) [see section 4]. The selectivity for MAO-B inhibition diminishes in a dose-related manner as the dose of rasagiline is elevated above the recommended daily dose.[11]

2.1 Neuroprotective Effects

The process of apoptosis can be induced either by DNA damage, improperly folded proteins or the withdrawal of cell survival factors (intrinsic pathway), or by external ligands (extrinsic pathway).[2] Regardless of whether apoptosis is initiated via the intrinsic or extrinsic pathway, a large family of cysteine proteases known as caspases executes the apoptotic programme.[2] In patients with Parkinson’s disease, an increase in activated caspase 3 (a pro-apoptotic catalyst) and apoptosis-related genes and the presence of fragmented nuclei in the brain permits the detection of apoptosis.[17]

Rasagiline has demonstrated neuroprotective properties in both in vitro and in vivo models of Parkinson’s disease and other neurodegenerative disorders;[17] according to structural-activity studies, this effect is associated with the propargyl moiety of rasagiline.[18] Of note, the S-enantiomer of rasagiline, which lacks MAO-B inhibitory activity, has demonstrated neuroprotective effects in vitro and in vivo, indicating a MAO-B independent mechanism.[7,9,17]

The neuroprotection of rasagiline is attributed to the direct stabilization of mitochondrial membranes and the induction of anti-apoptotic prosurvival genes.[7,17] In preclinical studies, rasagiline prevented the opening of mitochondrial permeability transition (mPT) pore complexes, mitochondrial swelling, the reduction in mitochondrial membrane potential, the release of cytochrome C and the subsequent suppression of a number of apoptotic stages, including caspase activation and the nuclear translocation of glyceraldehyde-3-phosphate-dehydrogenase (GAPDH).[7,17] MAO-B inhibitors have also been shown to elevate the transcription of prosurvival genes through the activation of the nuclear transcription factor system.[17]

The major active metabolite of rasagiline is 1-aminoindan (see section 3).[10] As reviewed by Oldfield et al.,[9] 1-aminoindan does not inhibit the anti-apoptotic activity of rasagiline and exerts no sympathomimetic activity. There is also evidence from a recently published in vivo study[19] to suggest that it may induce neuroprotective effects. In this study, 1-aminoindan reversed behavioural asymmetry, restored striatal catecholamine levels and significantly (p < 0.05) protected neurons from hydrogen peroxide-induced oxidative stress in the rat models of Parkinson’s disease.[19]

3. Pharmacokinetic Properties

The pharmacokinetic properties of oral rasagiline have been discussed in detail previously;[8,9] this section provides a brief summary. Discussion focuses predominantly on data from the EU summary of product characteristics (SPC)[10] and the US prescribing information,[11] supplemented with data from a study in patients with Parkinson’s disease.[14]

Rasagiline exhibits linear pharmacokinetics in the 0.5–2 mg dose range.[10] The pharmacokinetics of multiple doses of rasagiline as an adjunct to levodopa in patients with Parkinson’s disease are presented in table I.
Table I

Pharmacokinetic parameters of oral rasagiline as an adjunct to levodopa in patients with Parkinson’s disease.[14] Rasagiline 0.5 mg/day (n = 21) or 1 mg/day (n = 18) was administered for 12 weeks and rasagiline 1 mg/day was administered for 1 week followed by rasagiline 2 mg/day for 11 weeks (n = 18)

Rasagiline is rapidly absorbed from the gastrointestinal tract, with an absolute bioavailability of ≈36%.[10,11] The bioavailability of rasagiline does not appear to be significantly affected by food with a high fat content.[10,11] Cmax was reached in ≈0.5–1.0 hours.[10,11]

After a single intravenous dose of rasagiline, the mean volume of distribution is 243 L.[10] The mean steady-state volume of distribution of oral[20] rasagiline was 87 L, suggesting that the tissue binding of rasagiline is in excess of plasma protein binding.[11] Following oral administration, approximately 60–70% of a single dose of 14C-labelled rasagiline was bound to plasma proteins.[10]

Rasagiline undergoes almost complete biotransformation in the liver; biotransformation involves two major metabolic pathways, N-dealkylation and/or hydroxylation, which yield 1-aminoindan, 3-hydroxy-N-propargyl-1-aminoindan and 3-hydroxy-1-aminoindan.[10,11] In vitro studies have suggested that both major metabolic pathways depend upon the cytochrome P450 (CYP) system, with CYP1A2 the major isoenzyme involved in rasagiline metabolism.[10,11]

The terminal elimination t1/2 is 0.6–2 hours.[10] The conjugation of rasagiline and its metabolites to glucuronides, with subsequent urinary excretion, has been identified as the major elimination pathway.[10,11] The elimination of 14C-labelled rasagiline occurs primarily via the urine (63% and 22% of the total dose is excreted via the urine and faeces), with a total calculated recovery of 84% of the dose over 38 days.[10] Less than 1% of 14C-labelled rasagiline is excreted unchanged in the urine.[10,11]

3.1 Special Populations

Age and sex do not appear to affect the pharmacokinetics of rasagiline in adult patients,[11] and dosage adjustments are not required in the elderly.[10,11]

The pharmacokinetics of rasagiline (including bioavailability) in patients with mild or moderate renal impairment are similar to those observed in healthy volunteers.[10,11] No dosage adjustment is required in patients with renal impairment in the EU[10] or in patients with mild to moderate renal impairment in the US (data are lacking in patients with severe renal impairment).[11]

Rasagiline exposure is increased in patients with hepatic impairment.[10,11] Following oral administration of rasagiline 1 mg/day for 7 days, area under the concentration-time curve (AUC) and Cmax were elevated 2- and 1.4-fold in patients with mild hepatic impairment (Child-Pugh score of 5–6) and 7- and 2-fold in patients with moderate hepatic impairment (Child-Pugh score of 7–9) compared with healthy volunteers.[11] Therefore, in the US, a rasagiline dosage of 0.5 mg/day is recommended in patients with mild hepatic impairment, and rasagiline should not be utilized in patients with moderate or severe hepatic impairment.[11] The EU SPC recommends caution when administering rasagiline to patients with mild hepatic impairment; the use of rasagiline should be avoided in patients with moderate hepatic impairment and is contraindicated in patients with severe hepatic impairment.[10]

4. Drug Interactions

Data from in vitro studies indicate that rasagiline is not expected to induce clinically relevant pharmacokinetic interactions with substrates of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A,[10,11] with the coadministration of rasagiline and theophylline (a substrate of CYP1A2) not affecting the pharmacokinetics of either agent.[11] However, the concurrent administration of rasagiline and the CYP1A2 inhibitor ciprofloxacin resulted in an 83% elevation in the rasagiline AUC value, but no change in the elimination t1/2.[11] Moreover, plasma rasagiline concentrations may be reduced in smokers owing to the induction of CYPA12.[10] The US prescribing information recommends a rasagiline dosage of 0.5 mg/day in patients receiving concomitant therapy with ciprofloxacin or another CYP1A2 inhibitor.[11] The EU SPC recommends that potent CYP1A2 inhibitors be administered with caution to patients receiving rasagiline.[10]

Although conflicting data have been reported from population pharmacokinetic studies on the effect of levodopa on rasagiline clearance, this effect appears to be modest and adjustment of the rasagiline dosage is therefore not required.[11]

Serious adverse events (defined as severe, occasionally fatal, CNS toxicity associated with hyperpyrexia [as part of the serotonin syndrome][11]) have been reported with the concomitant administration of selective MAO-B and/or non-selective MAO inhibitors and an antidepressant (including serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors [SSRIs] or tricyclic, tetracyclic or triazolopyridine antidepressants).[10,11] The number of patients concomitantly exposed to rasagiline, as monotherapy or as adjunctive therapy to levodopa, and antidepressants (SSRIs, n = 141; tricyclics, n = 115) across nine studies in patients with early (including TEMPO and ADAGIO [see section 5.1 for study design and full treatment regimen details]) or advanced (including LARGO and PRESTO [see section 5.2 for study design and full treatment regimen details]) Parkinson’s disease[21] was not sufficient to exclude the potential for a drug interaction. Therefore, although the EU SPC advises caution when rasagiline is administered concomitantly with antidepressants, coadministration with fluoxetine and fluvoxamine should be avoided.[10] According to the US prescribing information, the concomitant administration of rasagiline and antidepressants should be avoided.[11] Of note, a recent multicentre, retrospective study (STACCATO) [currently available as an abstract] found no occurrences of serotonin toxicity following the concomitant administration of rasagiline and an antidepressant in patients with Parkinson’s disease.[22,23]

Serious adverse events have also been reported following the concurrent administration of MAO inhibitors, including selective MAO-B inhibitors, and cyclobenzaprine, dextromethorphan, dextropropoxyphene, methadone, pethidine (merperidine) and/or tramadol;[10,11] the concomitant administration of rasagiline and these drugs is contraindicated in the US.[11] In the EU, the coadministration of rasagiline and pethidine is contraindicated and the coadministration of rasagiline and dextromethorphan is not recommended.[10]

The risk of nonselective MAO inhibition, which may result in a hypertensive crisis, is elevated following concurrent therapy with rasagiline and other MAO inhibitors.[10,11] Therefore, concomitant therapy with other MAO inhibitors (including medicinal/natural products [e.g. hypericum (St. John’s wort)]) is contraindicated.[10,11]

Although hypertensive responses are not expected following the coadministration of rasagiline and sympathomimetic agents (such as those present in nasal, oral and ophthalmic decongestants or cold medicine products),[11] their coadministration is not recommended by the EU SPC,[10] whereas the US prescribing information[11] advises caution.

4.1 Tyramine

Despite the fact that tyramine is a substrate of both MAO-A and MAO-B isoenzymes, it is MAO-A that is primarily responsible for its intestinal metabolism.[24] Tyramine engenders a pressor effect via the release of noradrenaline from sympathetic neurons innervating cardiac tissues and vascular smooth muscle; thus, a hypertensive ‘cheese’ reaction (so called because of the high levels [i.e. >150 mg] of tyramine present in aged cheese) may arise following the excessive absorption of dietary tyramine in patients receiving the recommended dose of rasagiline because of a mild increase in tyramine sensitivity.[11,24]

Data from five tyramine challenge studies in healthy volunteers and in patients with Parkinson’s disease (including in the TEMPO[25,26] and PRESTO[27] studies discussed in section 6), the home monitoring of post-meal BP levels in patients with Parkinson’s disease and the lack of tyramine-rasagiline interaction reports in clinical studies conducted without tyramine restriction indicate that rasagiline can be utilized without restrictions in dietary tyramine.[10] Notably, data from a recent tyramine challenge study[16] that revealed the MAO-B selectivity of rasagiline 1 mg/day generated the removal of dietary tyramine restrictions from the US prescribing information. However, while restrictions in dietary tyramine are not ordinarily required with the recommended doses of rasagiline, the US prescribing information advises patients to avoid the consumption of foods containing large amounts of tyramine.[11]

5. Therapeutic Efficacy

5.1 Monotherapy

The therapeutic efficacy of oral rasagiline monotherapy in patients with early Parkinson’s disease was assessed in two large (n > 400 per study) randomized, double-blind, placebo-controlled, multinational studies: TEMPO[25,26] (section 5.1.1) and ADAGIO[28] (section 5.1.2) [see table II for study acronym definitions], with ADAGIO[28] evaluating the potential effects of rasagiline on the slowing of clinical progression. Both studies utilized a delayed start design.[25,26,28] The effect of rasagiline therapy on health-related quality of life (HR-QOL) in the TEMPO study is also summarized.[29] Long-term efficacy in an up to 5.5 years’ noncomparative extension period[30,31] (up to 6.5 years’ total duration of rasagiline therapy) of the TEMPO study[25,26] and additional data from prespecified and post hoc analyses[32] of the ADAGIO study[28] are discussed. Limited additional data were available as data on file.[20]
Table II

Study acronyms

Patients in the ADAGIO and TEMPO studies had early Parkinson’s disease with at least two of the three cardinal features of the disorder (bradykinesia, resting tremor, rigidity).[25,26,28] Study design details (including inclusion and exclusion criteria) and baseline patient characteristics are presented in table III.
Table III

Features of randomized, double-blind, multinational studies in patients with early Parkinson’s disease

5.1.1 TEMPO

The double-blind period of the TEMPO study was performed in two phases: in the first (placebo-controlled) phase, patients were randomized to receive rasagiline 1 mg/day (n = 134) or 2 mg/day (n = 132) [early-start treatment groups] or placebo (n = 138) for 26 weeks, with all rasagiline recipients initially receiving the 1 mg/day dosage for the first week.[25,26] In the second (active treatment) phase, patients who had received rasagiline 1 or 2 mg/day for 26 weeks continued therapy with rasagiline (1 mg/day, n = 122; 2 mg/day, n = 119) for a further 26 weeks, while patients who had initially received placebo switched to rasagiline 2 mg/day for 26 weeks (n = 130) [delayed-start treatment group].[25,26] Those patients requiring additional (dopaminergic) therapy in the placebo-controlled phase could enter the active treatment phase earlier than prespecified; those patients requiring additional therapy in the active treatment phase received either a combination of carbidopa and levodopa or a dopamine agonist.[25,26]

Those patients who completed the double-blind period were eligible to enter a nonblind extension period of up to 5.5 years’ duration (up to 6.5 years’ total duration of rasagiline therapy) [early-start rasagiline treatment group, n = 198; delayed-start rasagiline treatment group, n = 108].[30,31] Patients (and the study investigators) who entered the nonblind extension period phase remained blinded as to their study medication in the placebo- and active-controlled phases. During this extension period, all patients initially received rasagiline 2 mg/day (mean duration 15.8 months) before being switched to rasagiline 1 mg/day (mean duration 34.1 months) following analysis of the 6-month efficacy data, which demonstrated no difference between the two dosages.[30,31] Additional antiparkinsonian therapy (apart from selegiline) was permitted.[30] The average duration in the TEMPO study for all patients was 3.6 years.[30]

The primary efficacy endpoint is detailed in table III. Secondary endpoints included the change from baseline in the Unified Parkinson’s Disease Rating Scale (UPDRS) activities of daily living (ADL), mental and motor subscale scores and symptom-based subscores (e.g. bradykinesia, postural instability/gait disorder [PIGD], rigidity and tremor), the change from baseline in the Hoehn and Yahr stage, Beck Depression Inventory (BDI), Schwab and England ADL scale, Parkinson’s Disease Quality of Life (PDQUALIF) scale and the timed motor scores, and/or the proportion of patients responding to therapy (those patients who experienced a worsening in the total UPDRS score of less than 3 points from baseline to week 26 or a worsening of less than 4 points from baseline to week 52).[25,26]

Data are reported for the modified intent-to-treat (ITT) population (all enrolled patients with post-randomization data [placebo-controlled phase] or all patients with at least one efficacy assessment [active treatment phase]), utilizing the last observation carried forward (LOCF) to impute missing data.[25,26]

Monotherapy with rasagiline 1 and 2 mg/day was effective in patients with Parkinson’s disease, conferring a significant (p < 0.001) benefit over placebo in terms of the adjusted (for baseline UPDRS score and rating investigator) mean change from baseline to week 26 in the total UPDRS score (primary efficacy analysis) [figure 1].[25] At 26 weeks, the unadjusted mean total UPDRS scores were 24.8, 26.6 and 28.4 in the rasagiline 1 and 2 mg/day and placebo treatment groups, respectively.[25] The unadjusted mean changes from baseline in the total UPDRS scores in the respective treatment groups were 0.1, 0.7 and 3.9.[25]
Fig. 1a

Efficacy of oral rasagiline monotherapy in patients with Parkinson’s disease. Results of the double-blind, multinational TEMPO study;[25,26] patients received rasagiline 1 mg/d (n = 134) or 2 mg/d (n = 132) or placebo (n = 138) for 26 weeks (placebo-controlled phase). At 26 weeks, patients in the placebo group switched to rasagiline 2 mg/d (delayed-start treatment group; n = 130) whereas all other patients continued their original therapy (rasagiline 1 mg/d [n = 122] or 2 mg/d [n = 119]) for an additional 26 weeks (active-treatment phase). Differences for mean-adjusted (adjusted for baseline Unified Parkinson’s Disease Rating Scale [UPDRS] score and rating investigator) changes from baseline in UPDRS total (primary endpoint) and subscale scores relative to (a) placebo at 26 weeks[25] and to (b) delayed-start rasagiline 2 mg/d at 52 weeks[26] in the intent-to-treat populations (primary endpoint analyses). ADL = activities of daily living; BL = baseline; DS = delayed start; PIGD = postural instability/gait disorder; PL = placebo; pts = patients; RAS = rasagiline; UPDRS = Unified Parkinson’s Disease Rating Scale; * p < 0.05, ** p < 0.001 vs PL; † p = 0.05, †† p = 0.01, ††† p = 0.005 vs DS RAS 2 mg/d. Adapted from Oldfield V, Keating GM, Perry CM. Rasagiline: a review of its use in the management of Parkinson’s disease. Drugs 2007; 67 (12): 1725-47 with permission from Adis (© Adis Data Information BV 2007. All rights reserved.).

A significantly slower rate of worsening favouring rasagiline 1 and 2 mg/day over placebo was also observed in terms of the adjusted mean changes from baseline to week 26 in UPDRS ADL and motor, but not mental, subscale scores (figure 1) and in the bradykinesia subscores (−1.51 [95% CI −2.19, −0.82] and −0.77 [95% CI −1.47, −0.08]) [figure 1].[25] Moreover, the adjusted mean change from baseline to week 26 in the tremor subscore indicated a significantly slower rate of worsening with rasagiline 1 mg/day (−0.63 [95% CI −1.03, −0.23]), but not 2 mg/day (−0.38 [95% CI −0.78, 0.02]), than with placebo (figure 1). However, no significant differences between the rasagiline 1 or 2 mg/day and the placebo treatment groups with respect to the adjusted mean change from baseline to week 26 in the UPDRS PIGD and rigidity subscores (figure 1), and in the Schwab and England ADL scale, Hoehn and Yahr stage, BDI and timed motor scores were observed.[25]

At 26 weeks, the proportion of patients responding to therapy was significantly higher following monotherapy with rasagiline 1 mg/day (p = 0.004) and 2 mg/day (p = 0.001) than with placebo (66% and 67% vs 49%).[25]

Additional antiparkinsonian therapy (levodopa) during the 26-week placebo-controlled phase was required by 11.2% of rasagiline 1 mg/day recipients, 16.7% of rasagiline 2 mg/day recipients and 16.7% of placebo recipients.[25] No statistically significant differences in the time to the requirement for additional antiparkinsonian therapy was observed among the three treatment groups.[25]

Compared with delayed-start rasagiline 2 mg/day, beneficial effects in terms of the adjusted mean change from baseline in the total UPDRS score were reported following 52 weeks’ therapy with early-start rasagiline 2 mg/day, but not 1 mg/day (primary efficacy analysis) [figure 1].[26] At 52 weeks, the mean total UPDRS scores were 27.45 and 27.10 in the early-start rasagiline 1 and 2 mg/day treatment groups and 28.02 in the delayed-start rasagiline 2 mg/day treatment group.[26] The mean changes from baseline to week 52 in the total UPDRS scores in the respective treatment groups were 3.01, 1.97 and 4.17.[26]

At 52 weeks, a significant between-group difference favouring rasagiline 2 mg/day, but not 1 mg/day, over placebo was observed in the change from baseline in the UPDRS ADL subscale score (figure 1).[26] However, therapy with rasagiline 1 and 2 mg/day had no significant effect on the adjusted mean change from baseline to week 52 in UPDRS mental and motor subscale scores and the Hoehn and Yahr stage and Schwab and England ADL scale scores.[26]

No differences in the time to the requirement for additional antiparkinsonian therapy was observed at week 52 among the three treatment groups (no quantitative data reported).[26] Moreover, the proportion of patients responding to therapy was significantly higher following monotherapy with rasagiline 2 mg/day (63.9%; p = 0.04), but not 1 mg/day (52.5%), than with delayed-start rasagiline 2 mg/day (52.3%).[26]

Compared with delayed-start rasagiline therapy, early initiation was associated with a slower long-term progression of the clinical signs and symptoms of Parkinson’s disease over the 6.5 years of the TEMPO study.[30] The adjusted mean between-group difference in the change from baseline to 6.5 years in the total UPDRS score (2.5 points) significantly (p = 0.021) favoured early-start rasagiline therapy over delayed-start rasagiline therapy, with a corresponding mean relative between-group difference in the percentage change from baseline of 16% (p = 0.006), indicating less functional decline. The interaction between treatment and time was significant for both analyses: p = 0.0146 for the change in the total UPDRS score and p = 0.0126 for the percentage change in the total UPDRS score. A significant (p < 0.05) between-group difference in the percentage change from baseline in the total UPDRS score was also observed at various half-yearly timepoints: 0.5, 1.5, 2.0, 3.0, 4.5, 5.0 and 5.5 years. Significant mean between-group differences in the percentage change from baseline to 6.5 years in the UPDRS ADL (39.1%; p = 0.028) and motor scores (11.9%; p = 0.046) [indicating less worsening] favouring early-start rasagiline over delayed-start rasagiline were also observed.[30]

No statistically significant difference was observed between early-start and delayed-start rasagiline recipients in the mean dose of levodopa required at any timepoint or the median time from baseline to the addition of dopaminergic therapy (1.5 and 1.8 years).[30]

According to Kaplan-Meier estimates, no significant differences between early-start and delayed-start rasagiline were predicted in the earliest time to either dyskinesia or fluctuations, the median time to fluctuations and the time for 25% of patients to experience dyskinesia.[30]

In the nonblind extension period, the absolute percentages of patients who were maintained on rasagiline monotherapy and who did not require additional dopaminergic therapy at 2, 4 and 6 years were 46% (122 of 266 patients), 23% (46 of 204) and 13% (3 of 23).[31] Over 70% of patients requiring additional dopaminergic therapy commenced treatment with a dopamine agonist.[31] The percentage of rasagiline recipients receiving concomitant levodopa therapy gradually increased, from 10.9% at year 2 to 17.4% at year 6, with 60.9% of patients receiving rasagiline plus levodopa plus a dopamine agonist at year 6.[31]

Health-Related Quality of Life

Compared with placebo, therapy with rasagiline 1 and 2 mg/day significantly improved HR-QOL, as assessed by the PDQUALIF questionnaire, over the 26-week placebo-controlled phase of the TEMPO study (n = 404, with those patients entering the active treatment phase early having their PDQUALIF score carried forward to week 26).[29] The PDQUALIF consists of 32 questions scored on a five-point Likert scale, with scores ranging from 0 to 128 (higher scores indicate a worse HR-QOL).[29] Seven domain subscores were calculated: independence, outlook, physical function, sleep, self-image/sexuality, social role and urinary function.[29]

Improvements (adjusted mean change from baseline to week 26) in total PDQUALIF scores were significantly greater with rasagiline 1 mg/day (p = 0.01) and 2 mg/day (p = 0.02) than with placebo (−0.36 and −0.19 vs +2.55).[29] Mean baseline scores in the respective treatment groups were 28.3, 30.2 and 26.9.[29] The between-group difference in the change from baseline in the total PDQUALIF score significantly favoured rasagiline 1 mg/day (−2.91 [95% CI −5.19, −0.64]; p = 0.01) and 2 mg/day (−2.74 [95% CI −5.02, −0.45]; p = 0.02) over placebo, with the observed between-group differences apparently driven by significant between-group differences in the self-image/sexuality domain subscore (p = 0.0001 and 0.008 for rasagiline 1 and 2 mg/day vs placebo).[29]

The duration of rasagiline therapy does not appear to influence HR-QOL, with no significant differences observed between the early-start rasagiline 1 and 2 mg/day recipients and the delayed-start rasagiline 2 mg/day recipients at study end (week 52; n = 266). At this timepoint, the adjusted mean changes from baseline in total PDQUALIF scores in the respective treatment groups were 0.27, 2.28 and 0.54.[29] The changes from baseline in total PDQUALIF scores observed in delayed-start rasagiline 2 mg/day recipients were consistent with those observed in early-start rasagiline 1 and 2 mg/day recipients, suggesting that the beneficial effects of rasagiline on HR-QOL are induced via a symptomatic effect.[29] However, this study was not powered to detect whether a slowing of clinical progression (if present) affected HR-QOL outcomes, with the length of the study potentially insufficient to permit the emergence of meaningful differences.[29]

5.1.2 ADAGIO

In the first, 36-week placebo-controlled, phase of the ADAGIO study, 1176 patients with early, untreated Parkinson’s disease were randomized to one of four treatment groups: rasagiline 1 or 2 mg/day (early-start treatment groups) or the corresponding placebo.[28] In the second, active treatment, phase, patients who had received rasagiline 1 or 2 mg/day for 36 weeks (early-start treatment groups) continued therapy with rasagiline for a further 36 weeks, while patients who had initially received placebo for 36 weeks switched to rasagiline 1 or 2 mg/day for the next 36 weeks (delayed-start treatment groups).[28] Patients requiring additional therapy in the placebo-controlled phase could proceed directly to the active treatment phase; patients requiring additional therapy in the active treatment phase were withdrawn from the study.[28]

The primary efficacy analysis comprised three hierarchical endpoints based on the change from baseline in the total UPDRS score (table IV).[28] All three primary efficacy endpoints had to be met for each dose for the study to be declared positive.[28] Of note, the power calculation for the sample size was based on that utilized in the TEMPO study:[25,26] the mean change from baseline in the UPDRS score between the early-start and delayed-start treatment groups from weeks 48 to 72.[28]
Table IV

Definition of primary and secondary endpoints assessed in the multinational ADAGIO study.[28] Limited additional data were available as data on file[20]

Data are reported for the modified ITT population (all patients who underwent evaluations at baseline and week 12 or later [first primary endpoint]; all patients who received at least 24 weeks’ therapy during the placebo-controlled phase and who underwent evaluations at week 48 or later [second and third primary endpoints]).[28]

Rasagiline 1 mg/day, but not 2 mg/day, met all three hierarchical primary endpoints in the treatment of patients with Parkinson’s disease (figure 2).[28] The mean estimated rate of change in the UPDRS score per week from weeks 12 to 36 (first primary endpoint) indicated a significantly (p ≤ 0.01) slower rate of worsening (i.e. an increase in the UPDRS score) with rasagiline 1 or 2 mg/day than placebo (figure 2).[28] A significantly slower rate of worsening favouring early-start rasagiline 1 mg/day over delayed-start rasagiline 1 mg/day was also observed in terms of the second primary endpoint; however, no significant difference in this endpoint was observed between the early-start rasagiline 2 mg/day and delayed-start rasagiline 2 mg/day treatment groups (figure 2).[28] Based on the predefined noninferiority margin, early-start rasagiline 1 and 2 mg/day were considered to be noninferior to delayed-start rasagiline 1 and 2 mg/day with regard to the third primary endpoint (figure 2).[28]
Fig. 2

Efficacy of oral rasagiline monotherapy in patients with Parkinson’s disease. Results of the double-blind, multinational ADAGIO study;[28] see table IV and text for dosage and study design details. Results for the (a) first, (b) second and (c) third primary endpoints; analyses are for the modified intent-to-treat population. The between-group differences (95% CIs) are shown above the bars. DS = delayed start; ES = early start; NI = meets noninferiority criterion; PL = placebo; RAS = rasagiline; UPDRS = Unified Parkinson’s Disease Rating Scale; * p < 0.05, ** p = 0.01, *** p < 0.001 for the between-group difference.

The results obtained with rasagiline 1 mg/day (i.e. all three primary endpoints were met) suggest a slowing of the clinical progression of Parkinson’s disease for this dosage. However, given that the rasagiline 2 mg/day dosage did not meet the second primary endpoint, these results must be interpreted with caution (see also section 8).

Moreover, in terms of the secondary endpoint (see table IV for definition), rasagiline 1 mg/day (1.26 vs 4.27; between-group difference −3.01 [95% CI −3.86, −2.15]) and 2 mg/day (1.11 vs 4.27; between-group difference −3.15 [95% CI −4.00, −2.31]) were significantly (p < 0.001) more effective than placebo.[28]

Following an observed significant (p = 0.03) between-group (early-start vs delayed-start rasagiline 2 mg/day) difference in the second primary endpoint among those patients with a total UPDRS score at baseline in the highest quartile (>25.5) compared with those with a total UPDRS score at baseline in the lower three quartiles (≤25.5), the higher quartile and lower three quartile subgroups were analysed separately.[28] In the resulting post hoc analysis, both rasagiline 1 and 2 mg/day met all three primary endpoints in patients with a total UPDRS score at baseline in the highest quartile (n = 286 for the first primary endpoint and 219 for the second and third primary endpoints).[28] However, neither dose met all three primary endpoints in the subgroup of patients with a total UPDRS score at baseline in the lower three quartiles.

Compared with placebo, rasagiline 1 and 2 mg/day delayed the requirement for additional (symptomatic) antiparkinsonian therapy, according to a prespecified analysis.[32] Significantly fewer rasagiline 1 mg/day (25/288 [9%] vs 108/593 [18%]; odds ratio [OR] 0.41 [95% CI 0.25, 0.65; p = 0.0002]) and 2 mg/day (26/293 [9%] vs 108/593 [18%]; OR 0.41 [95% CI 0.26, 0.64; p = 0.0001]) recipients than placebo recipients required additional antiparkinsonian therapy during the placebo-controlled phase. The majority (≥89%) of patients in each treatment group requiring additional antiparkinsonian therapy were early converters (defined as patients who required additional antiparkinsonian therapy in the placebo-controlled phase and thus proceeded directly to the active-controlled phase). Moreover, a prespecified analysis of the time to requiring additional antiparkinsonian therapy resulted in estimated hazard ratios of 0.39 (95% CI 0.25, 0.60; p < 0.0001) and 0.38 (95% CI 0.24, 0.59; p < 0.0001) for the early-start rasagiline 1 and 2 mg/day treatment groups compared with placebo, suggesting an approximately 60% lower probability in requiring additional antiparkinsonian therapy in the early-start rasagiline treatment groups compared with the combined placebo group. The baseline UPDRS score was found to be a highly significant (p < 0.0001) covariate in the placebo-controlled phase for both the requirement of and the time to additional antiparkinsonian therapy.[32]

Further prespecified analyses found significantly greater progression in Parkinson Fatigue Scale[33] scores (mean change from baseline to the last observed value in the placebo-controlled phase) with placebo than with rasagiline 1 mg/day (−0.14; p = 0.0032) and 2 mg/day (−0.19; p < 0.0001).[32] There was a significant improvement in the non-motor experiences of daily living (draft version of Part 1 of the Movement Disorder Society-Sponsored Revision of the UPDRS [MDS-UPDRS]) scores[34] (mean change from baseline to the last observed value in the placebo-controlled phase) with rasagiline 1 mg/day (p = 0.049), but not rasagiline 2 mg/day, versus placebo.[32]

Moreover, post hoc analyses demonstrated significant (p < 0.005) differences favouring rasagiline 1 mg/day over placebo in the mean change from baseline to week 36 in the UPDRS ADL, mental and motor subscale scores (corresponding to a percentage subscore contribution to the treatment effect of 29%, 7% and 64%, respectively) and a significant (p = 0.035) difference favouring early-start rasagiline 1 mg/day over delayed-start rasagiline 1 mg/day in the mean change from baseline to week 72 in the UPDRS ADL subscale score (corresponding to a percentage subscore contribution to the treatment effect of 41%).[32] Significant (p < 0.0001) differences favouring rasagiline 2 mg/day over placebo were also observed in the mean change from baseline to week 36 in the UPDRS ADL and motor subscale scores (corresponding to a percentage subscore contribution to the treatment effect of 28% and 70%, respectively). However, no significant differences between early-start rasagiline 1 mg/day and delayed-start rasagiline 1 mg/day in the mean change from baseline to week 72 in the UPDRS mental and motor subscale scores (corresponding to a percentage subscore contribution to the treatment effect of 8% and 51%, respectively), between rasagiline 2 mg/day and placebo in the mean change from baseline to week 36 in the UPDRS mental subscale score (corresponding to a percentage subscore contribution to the treatment effect of 3%) and between early-start rasagiline 2 mg/day and delayed-start rasagiline 2 mg/day in the mean change from baseline to week 72 in the UPDRS ADL, mental and motor subscale scores were observed (percentage subscore contribution to the treatment effect not calculated as the total treatment effect was not significant).[32]

5.2 As Adjunctive Therapy to Levodopa

Two large (n > 450 per study) double-blind, multinational studies (LARGO[35] and PRESTO;[27] acronyms defined in table V) assessed the efficacy of oral rasagiline as adjunctive therapy to levodopa in patients with Parkinson’s disease and motor fluctuations. Limited supplementary data for both studies have been procured from a previous review[9] and/or the US prescribing information,[11] with data from a substudy[36] of the LARGO study[35] and a post hoc analysis[37] of data from the LARGO[35] and PRESTO[27] studies also discussed.
Table V

Study acronyms

Data from the LARGO and PRESTO studies were supported by those from a post-marketing, multicentre, observational study in 754 patients with idiopathic Parkinson’s disease who received rasagiline 1 mg/day for a mean of 118 days; 72% of patients received rasagiline in combination with another antiparkinsonian therapy.[38] Adjunctive therapy with rasagiline resulted in significant (p < 0.001) improvements from baseline in symptom severity, including motor and non-motor functions, as assessed by the Columbia University Rating Scale, and HR-QOL, as assessed by the Parkinson’s Disease Questionnaire-39, and a significant (p < 0.001) reduction from baseline in the median daily ‘off’ time.[38]

Key inclusion and exclusion criteria and selected baseline characteristics of the LARGO and PRESTO studies are summarized in table VI.[27,35]
Table VI

Features of the randomized, double-blind, multinational LARGO and PRESTO studies investigating the efficacy of rasagiline as adjunctive therapy to levodopa in patients with idiopathic Parkinson’s diseasea and motor fluctuations

Upon completion of a 2- to 4-week levodopa optimization run-in phase in the LARGO study, patients were randomized to receive, as adjunctive therapy to levodopa, rasagiline 1 mg once daily, entacapone 200 mg (with each levodopa dose) or placebo for 18 weeks.[35] In the PRESTO study, patients, stratified by centre, were randomized to receive adjunctive therapy with rasagiline 0.5 mg/day, rasagiline 1 mg/day or placebo for 26 weeks.[27] In both studies, adjustments to the levodopa dose (reduction in the presence of worsening dyskinesia followed by a return to the original dose [but not beyond][35]) were permitted for the first 6 weeks of therapy.[27,35] No adjustments to the levodopa dose were permitted in the final 12[35] or 20[27] weeks of the studies.

The primary efficacy endpoint for the LARGO and PRESTO studies is detailed in table VI. The secondary efficacy analysis comprised the following hierarchical endpoints: the Clinical Global Impression (CGI) score[27,35] (see table VII for definition) during ‘on’ time,[35] the UPDRS ADL subscale score during ‘off’ time,[27,35] the UPDRS motor subscale score during ‘on’ time[27,35] and the PDQUALIF score.[27]
Table VII

Efficacy of oral rasagiline, as adjunctive therapy to levodopa, in patients with idiopathic Parkinson’s disease. Results of two randomized, double-blind, placebo-controlled, multinational studies (LARGO[35] and PRESTO[27]). Data are reported for the modified intent-to-treat population; see text and table VI for dosage and study design details

While analyses were conducted, where reported, in the modified ITT (all patients with at least one post-randomization visit or diary entry for that endpoint) [LOCF[27] for those endpoints that were not derived from the patients’ diaries[35]] and per-protocol (PP)[27] populations, only data from the modified ITT populations were described (as data from the PP analysis of the PRESTO study[27] were reported not to differ).

Adjunctive therapy with rasagiline 0.5[27] or 1[27,35] mg/day was effective in the treatment of patients with Parkinson’s disease, according to the primary efficacy analysis (table VII). Compared with placebo, significant reductions from baseline in the total daily ‘off’ time were observed with rasagiline 1 mg/day and entacapone 200 mg (in conjunction with levodopa) in the LARGO study[35] and with rasagiline 0.5 and 1 mg/day in the PRESTO study.[27] Moreover, significant between-group differences for both rasagiline 1 mg/day (p < 0.0001) and entacapone 200 mg (p = 0.0006) versus placebo were evident from week 6 in the LARGO study.[35] The changes from baseline and between-group differences were reported as being sustained throughout the treatment period of the PRESTO study (data presented in a figure; no statistical analysis reported).[27] The adjusted mean changes from baseline in the total daily ‘off’ time were −1.18 hours with rasagiline 1 mg/day, −1.20 hours with entacapone 200 mg and −0.40 hours with placebo in the LARGO study,[35] and −1.41 hours with rasagiline 0.5 mg/day, −1.85 hours with rasagiline 1 mg/day and −0.91 hours with placebo in the PRESTO study.[27]

In terms of the secondary efficacy analysis of the CGI score[27] during ‘on’ time,[35] the UPDRS ADL subscale score during ‘off’ time[27,35] and the UPDRS motor subscale score during ‘on’ time,[27,35] adjunctive therapy with rasagiline 0.5 mg/day,[27] rasagiline 1 mg/day[27,35] or entacapone 200 mg[35] was effective, with significant between-group differences observed in favour of the active treatments over placebo (table VII). At week 18 of the LARGO study, the adjusted mean change from baseline in the CGI score was −0.86, −0.72 and −0.37 in the rasagiline 1 mg/day, entacapone 200 mg and placebo treatment groups, respectively.[35] In the PRESTO study, rasagiline had no apparent effect on HR-QOL, with the change from baseline in the PDQUALIF score (secondary efficacy analysis) not significantly different from that observed with placebo (table VII).[27]

Moreover, according to a substudy (n = 105)[36] of the LARGO study,[35] a significant (p < 0.013) between-group difference favouring adjunctive therapy with rasagiline 1 mg/day, but not entacapone 200 mg, over placebo was observed in the least squares mean change from baseline in the UPDRS motor subscale score during ‘off’ time. However, no significant difference in this endpoint was observed between the rasagiline 1 mg/day and entacapone 200 mg treatment groups. At week 18, the least squares mean change from baseline in the UPDRS motor subscale score during ‘off’ time was −4.38 points (baseline 38.0 points) with rasagiline 1 mg/day, −1.95 points (baseline 39.4 points) with entacapone 200 mg and 1.27 points (baseline 40.3 points) with placebo.[36] No significant difference between the rasagiline 1 mg/day or entacapone 200 mg and placebo treatment groups with respect to the least squares mean change from baseline to week 18 in the UPDRS ADL subscale score during ‘off’ time was observed. At week 18, the least squares mean change from baseline in the UPDRS ADL subscale score during ‘off’ time was −1.89 points (baseline 18.3 points) with rasagiline 1 mg/day, −1.09 points (baseline 19.8 points) with entacapone 200 mg and −0.05 points (baseline 20.2 points) with placebo.[36]

In terms of the total daily ‘on’ time without dyskinesias, significant (p < 0.05) between-group differences in the adjusted mean change from baseline were seen for rasagiline 1 mg/day versus placebo (0.82 hours [95% CI 0.36, 1.27]) and for entacapone 200 mg versus placebo (0.82 hours [95% CI 0.36, 1.27]) in the LARGO study,[35] and for rasagiline 1 mg/day versus placebo (0.78 hours [95% CI 0.26, 1.31]) in the PRESTO study.[27] However, in terms of the total daily ‘on’ time with dyskinesias, a significant (p = 0.048) between-group difference was only observed in patients receiving rasagiline 1 mg/day versus placebo recipients in the PRESTO study (adjusted mean difference in the change from baseline of 0.37 hours [95% CI 0.00, 0.74]).[27]

In the PRESTO study, a significant (p = 0.02) between-group difference favouring rasagiline 1 mg/day, but not 0.5 mg/day, over placebo was observed in the change from baseline in the Schwab and England ADL scale score during ‘off’ time.[27] However, no significant difference between rasagiline 0.5 or 1 mg/day and placebo was observed in the change from baseline in the Schwab and England ADL scale score during ‘on’ time and in the change from baseline in the UPDRS ADL subscale score during ‘on’ time.[27]

The proportion of patients responding to therapy (those patients demonstrating a reduction from baseline of ≥1 hour in the mean total ‘off’ time per day) in the LARGO study was significantly (p < 0.01) higher following adjunctive therapy with rasagiline 1 mg/day and entacapone 200 mg than with placebo (51% and 45% vs 32%).[35] Moreover, the response to adjunctive therapy by rasagiline 1 mg/day and entacapone 200 mg recipients was accompanied by a significant (p < 0.01) reduction in the levodopa dosage compared with placebo (−24 and −19 vs +5 mg/day).[35]

In the PRESTO study, a reduction in the mean levodopa dosage of 32, 36 and 12 mg/day occurred in rasagiline 0.5 or 1 mg/day recipients and placebo recipients, respectively.[11,27]

According to a post hoc analysis[37] of data from the LARGO[35] and PRESTO studies,[27] the efficacy of rasagiline as adjunctive therapy in combination with levodopa was not affected by age (no interaction between age [≥70 or <70 years] and rasagiline was observed).

6. Tolerability

Oral rasagiline as monotherapy or as adjunctive therapy in combination with levodopa was generally well tolerated in patients with Parkinson’s disease.[25, 26, 27, 28,30,31,35,38] As the tolerability profile of rasagiline is well established, discussion in this section focuses on tolerability data derived from the multinational studies discussed in section 5.[25, 26, 27, 28,35] Supplementary data for the TEMPO[25,26] and PRESTO studies[27] have been procured from two retrospective analyses[39,40] and the US prescribing information,[11] with data from a post hoc analysis[37] of data from the LARGO[35] and PRESTO[27] studies also discussed.

The tolerability of rasagiline as monotherapy or as adjunctive therapy in combination with levodopa was not affected by age.[37,39] However, irrespective of therapy with rasagiline or placebo, patients aged ≥70 years experienced a significantly higher incidence of serious adverse events in the TEMPO (p = 0.04) and PRESTO (p = 0.02) studies, a significantly higher incidence of symptomatic orthostatic hypotension in the TEMPO study (p = 0.01) and a significantly higher incidence of hallucinations in the PRESTO study (p = 0.01) than patients aged <70 years.[39]

6.1 As Monotherapy

As monotherapy in patients with early Parkinson’s disease, the frequency and nature of treatment-emergent adverse events was generally similar across clinical studies and between the rasagiline and placebo groups.[25,28]

In the ADAGIO study, no significant differences between the rasagiline 1 or 2 mg/day and placebo treatment groups were observed in the incidence of adverse events related to dopaminergic therapy (figure 3).[28] Moreover, there were no significant between-group differences in the incidence of other adverse events occurring in more than 5% of rasagiline recipients (e.g. fatigue, back pain and headache).[28]
Fig. 3

Tolerability of oral rasagiline in patients with Parkinson’s disease. Incidence of dopaminergic adverse events in the placebo-controlled phase of the randomized, double-blind, multinational ADAGIO study;[28] see section 5.1.2 for dosage and study design details. PL = placebo; pts = patients; RAS = rasagiline.

For the most part, no significant differences in the incidence of individual treatment-emergent adverse events were observed between treatment groups in the placebo-controlled and active treatment phases of the TEMPO study.[25] Only the incidence of asthenia was significantly (p = 0.03) lower following therapy with rasagiline than with placebo (4.5% vs 10.9%) in the placebo-controlled phase.[25] In this phase, treatment-emergent adverse events were reported in 81.3% and 84.1% of rasagiline 1 and 2 mg/day recipients and 79.7% of placebo recipients, with treatment-emergent adverse events of a moderate or severe intensity experienced by 43.3%, 45.5% and 45.7% of patients, respectively.[25] In the active-controlled phase, treatment-emergent adverse events were reported in 66.4% and 60.5% of early-start rasagiline 1 and 2 mg/day recipients and 54.6% of delayed-start rasagiline 2 mg/day recipients, with treatment-emergent adverse events of a moderate or severe intensity experienced by 32.0%, 37.0% and 26.9% of patients, respectively.[26] The most frequently reported (>10% of rasagiline recipients) treatment-emergent adverse events were infection, headache and arthralgia in the placebo-controlled phase and infection in the active-controlled phase.[25,26]

A low (<4% of patients) incidence of cognitive and behavioural adverse events (i.e. confusion, hallucinations, sleep disorders/insomnia and somnolence) was observed following therapy with rasagiline 1 mg/day (n = 134), according to a retrospective analysis[40] of the TEMPO study.[25,26] Depression was reported in 5.2% (7 of 134 patients) of rasagiline 1 mg/day recipients and 2.2% (3 of 138) of placebo recipients.[40]

No significant differences in the incidence of early termination were observed between the rasagiline 1 and 2 mg/day and the placebo treatment groups in the placebo-controlled phase of the TEMPO study.[25]

Twenty serious adverse events (defined as hospitalizations or new malignancies) were reported in the placebo-controlled phase of the TEMPO study; six events occurred following therapy with rasagiline 1 mg/day, ten occurred following therapy with rasagiline 2 mg/day (with one patient in the rasagiline 2 mg/day treatment group experiencing two serious adverse events) and four occurred following therapy with placebo.[25] Melanoma and squamous cell carcinoma of the skin were diagnosed in one patient each in the early-start rasagiline 2 mg/day treatment group of the TEMPO study;[25] one patient in the early-start rasagiline 1 mg/day treatment group of the ADAGIO study had a melanoma at week 72.[28]

No significant differences in ECG abnormalities, laboratory test results, standing and supine pulse and standing and supine systolic and diastolic BP values were observed between the rasagiline 1 and 2 mg/day and placebo treatment groups in the placebo-controlled phase of the TEMPO study, with the exception of a significant (p = 0.02) elevation in supine systolic BP following therapy with rasagiline 2 mg/day, but not rasagiline 1 mg/day, versus placebo.[25]

No patient in the ADAGIO study experienced a serotonin or tyramine reaction.[28]

Long-term (up to 6.5 years’ treatment) therapy with rasagiline was generally well tolerated in patients with Parkinson’s disease.[30,31] Over the 5.5-year nonblind extension period[30] of the TEMPO study,[25,26] at least one treatment-emergent adverse event was observed in 97.7% (260 of 266 patients) of early-start rasagiline recipients and 99.2% (131 of 132) of delayed-start rasagiline recipients, with 10.5% and 11.4% of patients in the respective treatment groups withdrawing from therapy. The most frequently reported treatment-emergent adverse events included accidental injury, dizziness, infection and nausea.[30,31]

6.2 As Adjunctive Therapy to Levodopa

In the LARGO study, dopaminergic adverse events were observed in 22% of rasagiline 1 mg/day recipients, 27% of entacapone 200 mg recipients and 23% of placebo recipients, with the incidence of individual dopaminergic adverse events presented in figure 4.[35]
Fig. 4

Tolerability of oral rasagiline, as adjunctive therapy to levodopa, in patients with Parkinson’s disease. Incidence of (a) dopaminergic adverse events affecting ≥2% of patients in the randomized, double-blind, placebo-controlled, multinational LARGO study[35] and (b) treatment-emergent adverse events affecting ≥6% of patients in the rasagiline 0.5 or 1 mg/d treatment groups and that were numerically more frequent than in the placebo group in the randomized, double-blind, placebo-controlled, multinational PRESTO study;[11,27] see section 5.2 for dosage and study design details. ENT = entacapone; PL = placebo; pts = patients; RAS = rasagiline; * p < 0.05 vs PL; θ indicates an incidence of <1%.

In the PRESTO study, treatment-emergent adverse events were reported in 91% and 95% of rasagiline 0.5 and 1 mg/day recipients and 87% of placebo recipients.[27] The most frequently reported adverse events in the PRESTO study (difference between rasagiline 1 mg/day and placebo of ≥3%) included dyskinesia, accidental injury, nausea and fall (figure 4).[11]

Compared with placebo, therapy with rasagiline 1 mg/day was associated with a significantly (p < 0.05) higher incidence of anorexia (0.6% vs 5.4%), vomiting (figure 4) and weight loss (figure 4), and therapy with rasagiline 0.5 mg/day was associated with a significantly (p < 0.05) higher incidence of ataxia (figure 4).[11,27] Moreover, a significantly (p < 0.05) higher incidence of dyskinesia was observed in the combined rasagiline treatment group versus placebo (18% vs 10% of patients).[27] However, the incidence of depression was significantly (p < 0.05) lower in patients receiving rasagiline 0.5 mg/day than in those receiving placebo (quantitative data not reported).[27]

Serious adverse events occurred in 12 rasagiline 1 mg/day recipients, 12 entacapone 200 mg recipients and 17 placebo recipients in the LARGO study[35] and in 21 rasagiline 0.5 mg/day recipients, 18 rasagiline 1 mg/day recipients and 14 placebo recipients in the PRESTO study.[27] The most frequent serious adverse event in the PRESTO study was accidental injury.[27] One patient in the rasagiline 0.5 mg/day treatment group and two patients in the rasagiline 1 mg/day treatment group were diagnosed with melanoma during the PRESTO study.[27]

Treatment discontinuations occurred in 10%, 13% and 15% of patients receiving rasagiline 1 mg/day, entacapone 200 mg and placebo, respectively, in the LARGO study, with 7, 16 and 11 patients in the respective treatment groups discontinuing therapy because of adverse events.[35] In the PRESTO study, the incidence of therapy discontinuation because of a treatment-emergent adverse event did not significantly differ between the rasagiline 0.5 and 1 mg/day and placebo treatment groups, with approximately 9%, 7% and 6% of patients, respectively, discontinuing therapy because of a treatment-emergent adverse event.[11,27] Patients receiving rasagiline discontinued therapy owing to, among other events, diarrhoea, hallucination, rash and weight loss.[11]

According to a retrospective analysis[40] of the PRESTO study,[27] adjunctive therapy with rasagiline does not appear to result in significant behavioural and cognitive adverse events. The incidence of confusion, depression, hallucinations, sleep disorders/insomnia and somnolence was <9% in all patients, with the between-group difference (rasagiline 1 mg/day vs placebo) less than 1.7% (no statistical analysis reported).[40]

Adjunctive therapy with rasagiline appeared to have no effect on BP and pulse rate in the PRESTO study, although significantly (p < 0.05) more rasagiline 0.5 mg/day, but not rasagiline 1 mg/day, recipients than placebo recipients had low standing, but not supine, systolic and diastolic BP.[27] No significant differences between the treatment groups in ECG or laboratory values were observed.[27]

The incidence of dopaminergic adverse events following adjunctive therapy with rasagiline was independent of age (<70 or ≥70 years) and concomitant dopamine agonist therapy, according to a post hoc analysis of the LARGO study.[35] Moreover, in terms of the tolerability profile, there were no significant differences based on age or gender in the PRESTO study.[11]

7. Dosage and Administration

Oral rasagiline is available in the EU,[10] the US[11] and in several other countries worldwide, including Canada[41] and Israel.[42] The prescribing information for oral rasagiline differs across the countries in which it has been approved; therefore, this section focuses on the EU SPC[10] and the US prescribing information.[11] Local prescribing information should be consulted for detailed information, including contraindications, dosages, drug interactions, precautions and use in special patient populations.

In the EU,[10] oral rasagiline is indicated for the treatment of idiopathic Parkinson’s disease as monotherapy or as adjunctive therapy to levodopa in patients with end-of-dose fluctuations. The recommended dosage is 1 mg/day.[10] In the US,[11] oral rasagiline is indicated as monotherapy or as adjunctive therapy to levodopa for the treatment of adult patients with the signs and symptoms of idiopathic Parkinson’s disease. The recommended dosage of rasagiline as monotherapy is 1 mg/day; as adjunctive therapy to levodopa, the recommended initial dosage of rasagiline is 0.5 mg/day, with the dosage increased to 1 mg/day if a sufficient clinical response is not achieved with the 0.5 mg/day dosage.[11] Rasagiline may be administered with or without food.[10,11]

Recommendations, including dosage adjustments and contraindications, for the utilization of rasagiline in special patient populations and in terms of drug interactions are summarized in sections 3.1 and 4. Therapy with rasagiline is not recommended in children and adolescents owing to a lack of data.[10]

8. Place of Rasagiline in the Treatment of Idiopathic Parkinson’s Disease

The ultimate goal of an effective therapy for Parkinson’s disease is the slowing of disease progression.[1,5] However, to date, the neuroprotective effects demonstrated by various agents in animal models have not, for the most part, been translated into a slowing of the progression of Parkinson’s disease in clinical studies.[43,44] With current pharmacological therapies focusing on dopamine replacement to alleviate symptoms,[43,44] optimal symptomatic therapy would control the motor features of Parkinson’s disease without resulting in motor complications, possess long-term efficacy and an acceptable tolerability profile, and not require multiple dosing or a complicated administration schedule.

Although, following its advent, levodopa was considered the gold standard for the symptomatic treatment of Parkinson’s disease, it does not consistently alleviate all parkinsonian features, and its long-term utilization is associated with dose escalation and the development of motor complications (e.g. ‘on’/‘off’ fluctuations and dyskinesias).[3,5,6] However, its efficacy can be enhanced by the concomitant administration of other agents.[3,5] For instance, peripherally acting decarboxylase inhibitors (e.g. benserazide, carbidopa) can inhibit the conversion of levodopa to dopamine outside the CNS, thereby limiting systemic adverse events, and centrally acting MAO-B inhibitors (e.g. rasagiline, selegiline) can enhance dopaminergic effects by retarding the breakdown of levodopa-generated dopamine in the CNS.[3] Moreover, levodopa in an immediate-release form has a clearance half-life of 1–3 hours, which can be prolonged by the concomitant utilization of peripheral catechol-O-methyltransferase (COMT) inhibitors (e.g. entacapone, tolcapone).[3]

According to the UK National Institute for Health and Clinical Excellence (NICE) 2006 guidelines for the diagnosis and management of Parkinson’s disease[45] and the Joint European Federation of Neurological Societies (EFNS)/Movement Disorders-European Section (MDS-ES) 2011 guidelines on early (uncomplicated) Parkinson’s disease,[46] the requirements for each patient (i.e. their clinical and lifestyle characteristics, and preferences) should be considered prior to initiating therapy, as there is currently no consensus as to which agent(s) to utilize upon commencing the symptomatic therapy of Parkinson’s disease. Notably, symptomatic parkinsonian control and the prevention of motor complications are at the forefront of the therapeutic decision process.[46] Levodopa, an orally active dopamine agonist or a MAO-B inhibitor are recommended by the EFNS/MDS-ES 2011 guidelines[46] as options for initiating the symptomatic treatment of early Parkinson’s disease. The Scottish Intercollegiate Guidelines Network (SIGN) 2010 guidelines on the diagnosis and management of Parkinson’s disease[47] recommend levodopa in combination with a decarboxylase inhibitor, an oral or transdermal dopamine agonist, or a MAO-B inhibitor in these patients, with cholinergic receptor antagonists and ergot-derived dopamine agonists not recommended as first-choice agents.[47]

In terms of symptom control, MAO-B inhibitors exert a more modest effect than levodopa and (probably) dopamine agonists; however, levodopa is associated with the development of motor complications following several years of therapy.[46] Of note, the early utilization of the controlled-release formulation of levodopa is not effective in preventing the development of motor complications. The early utilization of levodopa is recommended in the older population as they are more sensitive to neuropsychiatric adverse events, but less prone to developing motor complications. The dopamine agonists pramipexole, piribedil and ropinirole are effective as monotherapy in the treatment of early Parkinson’s disease, with the risk of motor complications lower with pramipexole and ropinirole than levodopa. However, compared with levodopa, the beneficial effects of dopamine agonist therapy in preventing motor complications must be weighed against their symptomatic efficacy and their association with hallucinations, impulse control disorders, leg oedema and somnolence. Ergot-derived dopamine agonists (e.g. bromocriptine, cabergoline, pergolide) are not recommended as first-choice options because of the risk of fibrotic reactions, with therapy with subcutaneous apomorphine not appropriate at this stage of the disease. Amantadine and cholinergic receptor antagonists may also be utilized for the symptomatic treatment of early Parkinson’s disease; however, their effect on symptoms is less than that exerted by levodopa. Moreover, cholinergic receptor antagonists are poorly tolerated by elderly patients and thus their utilization is generally restricted to younger patients.[46]

Over time, patients with Parkinson’s disease develop motor and non-motor (e.g. autonomic dysfunction, dementia, falling, freezing episodes and postural instability) complications.[45,48] According to the EFNS/MDS-ES 2011 guidelines on late (complicated) Parkinson’s disease,[48] levodopa is the most important pharmacological component in the treatment of patients with advanced Parkinson’s disease, and is, owing to its lower (compared with dopamine agonists) propensity to induce hallucinations, the agent of choice in patients with advanced Parkinson’s disease with cognitive impairment and dementia.

For most patients, the symptomatic control of motor fluctuations will eventually require combination therapy, although there is insufficient evidence currently available on the combination of more than two strategies. The choice of agent(s) is based primarily on ease of utilization, experience of the clinician, patient preference and tolerability.[48] Options include adjusting the dosing frequency of levodopa or switching to the controlled-release formulation, the addition of a COMT inhibitor or a MAO-B inhibitor, the addition of a dopamine agonist, with non-ergot dopamine agonists recommended as first-line agents and pergolide and other ergot dopamine agonists as second-line agents (owing to their association with fibrotic reactions), and the addition of a cholinergic receptor antagonist (in younger patients) or amantadine.[48] A COMT inhibitor, a dopamine agonist or a MAO-B inhibitor are also recommended by the SIGN 2010 guidelines for the pharmacological management of motor complications in patients with advanced Parkinson’s disease.[47]

With respect to US-based guidelines, while current clinical evidence supports the utilization of MAO-B inhibitors as monotherapy in patients with early Parkinson’s disease or as adjunctive therapy to levodopa in patients with advanced Parkinson’s disease, the role of rasagiline at the time of publication of the American Academy of Neurology (AAN) 2002 guidelines on the initiation of treatment for Parkinson’s disease[49] was yet to be determined. Of note, the AAN is currently in the process of updating these guidelines.

The non-motor symptoms of Parkinson’s disease also result in significant morbidity and impaired HR-QOL; a range of agents are utilized to treat various non-motor symptoms of Parkinson’s disease, including depression, hallucinations, psychosis and sleep disturbances.[50] The AAN 2010 practice parameter[51] identified levodopa/carbidopa, polyethylene glycol and sildenafil for the treatment of spontaneous night-time leg movements, constipation and erectile dysfunction, respectively, but noted the lack of available data regarding the treatment of other non-motor symptoms, including anxiety, orthostatic hypotension and urinary incontinence. Recommendations for the symptomatic control of non-motor complications are also detailed in the EFNS/MDS-ES 2011 guidelines on late Parkinson’s disease.[48]

Rasagiline is a selective, irreversible MAO-B inhibitor, with such activity believed to increase striatal extracellular dopamine levels (section 2). Oral rasagiline, as monotherapy (section 5.1) or as adjunctive therapy to levodopa (section 5.2), was associated with symptomatic benefits in adult patients with Parkinson’s disease, according to the results of well designed studies.

In the TEMPO study, monotherapy with rasagiline 1 mg/day (recommended dosage) and 2 mg/day conferred a significant benefit over placebo in terms of the adjusted mean change from baseline to week 26 in the total UPDRS score (primary efficacy analysis), with beneficial effects reported with early-start rasagiline 2 mg/day, but not 1 mg/day, compared with delayed-start rasagiline 2 mg/day in terms of the adjusted mean change from baseline to week 52 in the total UPDRS score (primary efficacy analysis) [section 5.1.1]. Moreover, compared with delayed-start rasagiline therapy, early initiation was associated with a slower long-term progression of the clinical signs and symptoms of Parkinson’s disease, according to a nonblind extension of the TEMPO study (section 5.1.1). The duration of rasagiline therapy did not appear to influence HR-QOL, with no significant differences observed between the early-start rasagiline 1 and 2 mg/day recipients and the delayed-start rasagiline 2 mg/day recipients at week 52 (study end) of the TEMPO study (section 5). The changes from baseline in total PDQUALIF scores observed in delayed-start rasagiline 2 mg/day recipients were consistent with those observed in early-start rasagiline 1 and 2 mg/day recipients, suggesting that the beneficial effects of rasagiline on HR-QOL are induced via a symptomatic effect. However, this study was not powered to detect whether a slowing of clinical progression (if present) affected HR-QOL outcomes, with the length of the study potentially insufficient to permit the emergence of meaningful differences (section 5).

Discussion has arisen over the conflicting results observed with rasagiline 1 and 2 mg/day monotherapy in the ADAGIO study,[52, 53, 54, 55, 56] which utilized a delayed-start design in order to evaluate the potential effects of rasagiline on the slowing of clinical progression.[28] In this study, rasagiline 1 mg/day met all three hierarchical primary endpoints (see table IV for definitions); however, at the higher dosage of 2 mg/day, rasagiline met the first, but not the second, of the hierarchical primary endpoints (section 5.1.2). Interpreting these results is therefore difficult. The authors of the ADAGIO study noted that there were no significant differences in baseline characteristics and withdrawal rates between the two rasagiline dosage groups and suggested that a marked symptomatic effect following monotherapy with rasagiline 2 mg/day may have masked any slowing of clinical progression benefits associated with early-start therapy in the patient population studied[28] owing to the so-called ‘floor effect’ in the UPDRS scale.[44] Patients in the ADAGIO study[28] had a mean disease duration of 4.5 months and a mean total UPDRS score of 20.4, indicating mild disease, whereas those in the TEMPO study,[25] in which the rasagiline 2 mg/day dosage met the primary efficacy endpoint, had a mean disease duration of 11.0–13.8 months and a mean total UPDRS score of 24.5–25.9. The UPDRS floor is described as the maximum benefit recordable with the UPDRS scale,[44] with earlier studies demonstrating that the UPDRS scale favours the evaluation of moderate and severe disease, and thus may not be ideally suited for assessing the signs and symptoms associated with very mild disease.[57] Indeed, a post hoc analysis of data from the ADAGIO study found that rasagiline 2 mg/day met all three primary efficacy endpoints in the subgroup of patients with a total UPDRS score at baseline in the highest quartile (>25.5); however, neither dose met all three primary endpoints in the subgroup of patients with a total UPDRS score at baseline in the lower three quartiles (≤25.5) [section 5.1.2].

Moreover, doubt has also been raised as to the influence of potentially confounding factors intrinsic to the delayed-start study design.[52,54] Such factors include the possibility that modest changes may be overshadowed by other factors; the subjective components of the UPDRS scoring system; and the possibility that blinding may be broken prior to the end of the study.[52,54] In addition, as previously stated, the inclusion of patients with mild disease (in order to prevent large numbers of withdrawals) in conjunction with very slow disease progression challenges the study design to recognize differences between the treatment groups.[52,54] With respect to the ADAGIO study, patients who entered the active treatment phase, along with the study investigators, remained blinded as to their study medication in the placebo-controlled phase.[53] Moreover, a relatively low withdrawal rate (data not reported) was maintained, thus avoiding the confounding effect of a high withdrawal rate during the placebo-controlled phase on patients in the delayed-start treatment group, with randomization distributing patients with very early disease (who may have been misdiagnosed) across the treatment groups.[53] Notably, the delayed-start design was proposed in order to circumvent potential pharmacological or symptomatic confounding.[53] However, rather than specifically addressing mechanism, a positive result suggests that the observed benefits cannot be explained by a short-term symptomatic effect.[44] Long-term studies are required to assess the effect of an agent on cumulative disability,[53] with a follow-up study to ADAGIO underway to assess whether early-start rasagiline therapy (according to the ADAGIO study protocol) provided long-term benefits over delayed-start therapy.[58] The results are awaited with interest. Clearly, there is a need to more accurately measure the ability of antiparkinsonian agents to modify the disease. While it has been suggested that the UPDRS ADL subscale may be a more accurate marker of disease progression that other components of the UPDRS,[32] a measurable, validated biomarker that accurately reflects the underlying disease state would be ideal for evaluating the slowing of clinical progression.[44,52]

Adjunctive therapy with rasagiline 0.5 mg/day and 1 mg/day was effective in the symptomatic treatment of patients with Parkinson’s disease (section 5.2). Compared with placebo, significant reductions in total daily ‘off’ time were observed with rasagiline 1 mg/day and entacapone 200 mg (administered with each levodopa dose) in the LARGO study and with rasagiline 0.5 and 1 mg/day in the PRESTO study (table VII). Moreover, significant between-group differences for both rasagiline 1 mg/day and entacapone 200 mg versus placebo were evident from week 6 in the LARGO study, with the changes from baseline and between-group differences reported as being sustained throughout the treatment period of the PRESTO study (section 5.2).

As with levodopa and the vast majority of dopamine agonists,[52] rasagiline has demonstrated neuroprotective properties both in vitro and in vivo (section 2). This neuroprotection is attributed to the direct stabilization of mitochondrial membranes and the induction of anti-apoptotic prosurvival genes and, according to structural-activity studies, is associated with the propargyl moiety of rasagiline (section 2). However, identifying rasagiline’s potential to slow clinical progression in the clinical setting has been elusive to date and was not definitively demonstrated in the studies discussed in this article. Additional rasagiline studies specifically designed to assess the progression of Parkinson’s disease while addressing the potentially confounding factors of the delayed-start study design would therefore be of interest.

Limited data from relatively recent cost-effectiveness analyses based on Markov models suggest that rasagiline dominates (i.e. is more effective and less costly) some of the other oral treatments for Parkinson’s disease.[59,60] In patients with early Parkinson’s disease, a cost-utility analysis conducted from a UK healthcare payer perspective predicted that rasagiline monotherapy would dominate pramipexole monotherapy.[59] Over a period of 5 years, relative to pramipexole, rasagiline reduced mean direct costs by 18%, delayed the mean times to levodopa therapy by 25% and to the onset of dyskinesia by 10%, and generated a 5% gain in quality-adjusted life-years (QALYs).[59] The analysis incorporated efficacy data from the TEMPO study (section 5.1.1)[25,26] and a comparative study of pramipexole versus levodopa.[61] Likewise, in patients with advanced Parkinson’s disease, rasagiline as an adjunctive therapy to levodopa dominated standard care with levodopa, with regard to the incremental cost per QALY gained and the incremental cost per month with ≤25% ‘off’ time per day from both a societal and a healthcare payer perspective in the US.[60] Based on efficacy data from the LARGO study (section 5.2),[35,62] relative to standard care, adjunctive therapy with rasagiline was associated with mean incremental gains of 0.123 QALYs and 5.082 additional months with ≤25% ‘off’ time per day.[60]

As with all pharmacoeconomic analyses, these cost-effectiveness analyses have limitations, and the results cannot be generalized to other geographical locations. Further well designed pharmacoeconomic studies are needed to help clarify the relative cost effectiveness of rasagiline in the treatment of Parkinson’s disease.

Oral rasagiline as monotherapy or as adjunctive therapy in combination with levodopa was generally well tolerated in patients with Parkinson’s disease (section 6). In the ADAGIO study, the incidence of adverse events relating to dopaminergic therapy did not significantly differ between the rasagiline 1 or 2 mg/day and placebo treatment groups (figure 3).

Data indicate that Parkinson’s disease appears to be associated with a higher risk of skin cancer (not exclusively melanoma)[10] or melanoma.[11] Indeed, a recent meta-analysis[63] supports an association between Parkinson’s disease and a higher occurrence of melanoma. In the ADAGIO, TEMPO and PRESTO studies, between one and three rasagiline recipients were diagnosed with melanoma, with an additional rasagiline recipient in the TEMPO study diagnosed with squamous cell carcinoma (section 6). Thus, frequent monitoring is advised by the US prescribing information,[11] with the UK SPC[10] recommending that any suspicious skin lesion be evaluated by a specialist.

Rasagiline is associated with a number of drug interactions (section 4); therefore, local prescribing information should be consulted for detailed information on its concomitant utilization with other agents. Of note, restrictions in dietary tyramine are not generally required with recommended doses of rasagiline (section 4).

In conclusion, oral rasagiline as monotherapy or as adjunctive therapy to levodopa was effective in the symptomatic treatment of adult patients with Parkinson’s disease participating in double-blind, placebo-controlled, multinational studies. In patients with early Parkinson’s disease, monotherapy with rasagiline 1 or 2 mg/day significantly slowed the rate of worsening (i.e. an increase in the UPDRS score) in two studies, with the results for rasagiline 1 mg/day from one study suggesting a slowing of clinical progression. Compared with delayed-start rasagiline monotherapy, early initiation was associated with a slower long-term progression of the clinical signs and symptoms of Parkinson’s disease in one study. As adjunctive therapy to levodopa in patients with advanced Parkinson’s disease, rasagiline 0.5 or 1 mg/day significantly reduced the total daily ‘off’ time compared with placebo. As monotherapy or as adjunctive therapy to levodopa, rasagiline was generally well tolerated. Thus, oral rasagiline as monotherapy or as adjunctive therapy to levodopa provides a useful option in the treatment of adult patients with Parkinson’s disease.

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit.

References

  1. 1.
    Lees A. Alternatives to levodopa in the initial treatment of early Parkinson’s disease. Drugs Aging 2005; 22(9): 731–40PubMedCrossRefGoogle Scholar
  2. 2.
    Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill Medical, 2011Google Scholar
  3. 3.
    LeWitt PA. Levodopa for the treatment of Parkinson’s disease. N Engl J Med 2008 Dec; 359(23): 2468–76CrossRefGoogle Scholar
  4. 4.
    Clarke CE. Parkinson’s disease. BMJ 2007 Sep; 335(7617): 441–5PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Hauser RA, Zesiewicz TA. Advances in the pharmacologic management of early Parkinson disease. Neurologist 2007 May; 13(3): 126–32PubMedCrossRefGoogle Scholar
  6. 6.
    Elmer LW, Bertoni JM. The increasing role of monoamine oxidase type B inhibitors in Parkinson’s disease therapy. Expert Opin Pharmacother 2008 Nov; 9(16): 2759–72PubMedCrossRefGoogle Scholar
  7. 7.
    Jenner P, Langston JW. Explaining ADAGIO: a critical review of the biological basis for the clinical effects of rasagiline. Mov Disord 2011 Nov; 26(13): 2316–23PubMedCrossRefGoogle Scholar
  8. 8.
    Siddiqui MA, Plosker GL. Rasagiline. Drugs Aging 2005; 22(1): 83–91PubMedCrossRefGoogle Scholar
  9. 9.
    Oldfield V, Keating GM, Perry CM. Rasagiline: a review of its use in the management of Parkinson’s disease. Drugs 2007; 67(12): 1725–47PubMedCrossRefGoogle Scholar
  10. 10.
    Teva Pharma GmbH. Rasagiline (Azilect®): summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000574/WC500030048.pdf [Accessed 2011 Apr 12]
  11. 11.
    Teva Neuroscience Inc. Azilect® (rasagiline mesylate) tablets for oral use: prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021641s002s003s004s005s007s008s010lbl.pdf [Accessed 2011 Apr 12]
  12. 12.
    Youdim MB, Gross A, Finberg JP. Rasagiline [N-propargyl-1 R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol 2001 Jan; 132(2): 500–6PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Thébault JJ, Guillaume M, Levy R. Tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline: a potent, selective, and irreversible monoamine oxidase type B inhibitor. Pharmacotherapy 2004 Oct; 24(10): 1295–305PubMedCrossRefGoogle Scholar
  14. 14.
    Rabey JM, Sagi I, Huberman M, et al. Rasagiline mesylate, a new MAO-B inhibitor for the treatment of Parkinson’s disease: a double-blind study as adjunctive therapy to levodopa. Clin Neuropharmacol 2000 Nov-Dec; 23(6): 324–30PubMedCrossRefGoogle Scholar
  15. 15.
    Freedman NM, Mishani E, Krausz Y, et al. In vivo measurement of brain monoamine oxidase B occupancy by rasagiline, using 11C-L-deprenyl and PET. J Nucl Med 2005 Oct; 46(10): 1618–24PubMedGoogle Scholar
  16. 16.
    Goren T, Adar L, Sasson N, et al. Clinical pharmacology tyramine challenge study to determine the selectivity of the monoamine oxidase type B (MAO-B) inhibitor rasagiline. J Clin Pharmacol 2010 Dec; 50(12): 1420–8PubMedCrossRefGoogle Scholar
  17. 17.
    Naoi M, Maruyama W. Functional mechanism of neuroprotection by inhibitors of type B monoamine oxidase in Parkinson’s disease. Expert Rev Neurother 2009 Aug; 9(8): 1233–50PubMedCrossRefGoogle Scholar
  18. 18.
    Weinreb O, Bar-Am O, Amit T, et al. Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members. FASEB J 2004 Sep; 18(12): 1471–3PubMedGoogle Scholar
  19. 19.
    Weinreb O, Bar-Am O, Prosolovich K, et al. Does 1-(R)-aminoindan possess neuroprotective properties against experimental Parkinson’s disease? Antioxid Redox Signal 2011 Mar; 14(5): 767–75PubMedCrossRefGoogle Scholar
  20. 20.
    Teva Pharmaceutical Industries Ltd. Data on file. 2011 DecGoogle Scholar
  21. 21.
    Perez-Lloret S, Rascol O. Safety of rasagiline for the treatment of Parkinson’s disease. Expert Opin Drug Saf 2011 Jul; 10(4): 633–43PubMedCrossRefGoogle Scholar
  22. 22.
    Chen JJ, Panisett M, Rhyee S. Rasagiline and antidepressant use in patients with Parkinson’s disease: assessing the occurrence of serotonin toxicity [abstract]. 2011 Annual Meeting of the American College of Clinical Pharmacy; 2011 Oct 16–19; Pittsburgh (PA)Google Scholar
  23. 23.
    Teva Pharmaceutical Industries Ltd. Investigation of the occurrence of serotonin toxicity in Parkinson’s Disease (PD) patients treated concomitantly with rasagiline and antidepressants, using retrospective chart review [Clinical-Trials.gov identifier NCT00955604]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ [Accessed 2012 Jan 19]
  24. 24.
    Chen JJ, Swope DM, Dashtipour K. Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson’s disease. Clin Ther 2007 Sep; 29(9): 1825–49PubMedCrossRefGoogle Scholar
  25. 25.
    Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol 2002 Dec; 59(12): 1937–43CrossRefGoogle Scholar
  26. 26.
    Parkinson Study Group. A controlled, randomized, delayedstart study of rasagiline in early Parkinson disease. Arch Neurol 2004 Apr; 61(4): 561–6CrossRefGoogle Scholar
  27. 27.
    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): 241–8CrossRefGoogle Scholar
  28. 28.
    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 Sep; 361(13): 1268-PubMedCrossRefGoogle Scholar
  29. 78.
    Plus supplementary material available from URL: http://www.nejm.org/ [Accessed 2011 Mar 8]
  30. 29.
    Biglan KM, Schwid S, Eberly S, et al. Rasagiline improves quality of life in patients with early Parkinson’s disease. Mov Disord 2006 May; 21(5): 616–23PubMedCrossRefGoogle Scholar
  31. 30.
    Hauser RA, Lew MF, Hurtig HI, et al. Long-term outcome of early versus delayed rasagiline treatment in early Parkinson’s disease. Mov Disord 2009 Mar; 24(4): 564–73PubMedCrossRefGoogle Scholar
  32. 31.
    Lew MF, Hauser RA, Hurtig HI, et al. Long-term efficacy of rasagiline in early Parkinson’s disease. Int J Neurosci 2010 Jun; 120(6): 404–8PubMedCrossRefGoogle Scholar
  33. 32.
    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 May; 10(5): 415–23PubMedCrossRefGoogle Scholar
  34. 33.
    Brown RG, Dittner A, Findley L, et al. The Parkinson fatigue scale. Parkinsonism Relat Disord 2005 Jan; 11(1): 49–55PubMedCrossRefGoogle Scholar
  35. 34.
    Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008 Nov; 23(15): 2129–70PubMedCrossRefGoogle Scholar
  36. 35.
    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 Mar; 365(9463): 947–54PubMedCrossRefGoogle Scholar
  37. 36.
    Stocchi F, Rabey JM. Effect of rasagiline as adjunct therapy to levodopa on severity of OFF in Parkinson’s disease. Eur J Neurol 2011 Dec; 18(12): 1373–8PubMedCrossRefGoogle Scholar
  38. 37.
    Tolosa E, Stern MB. Efficacy, safety and tolerability of rasagiline as adjunctive therapy in elderly patients with Parkinson’s disease. Eur J Neurol 2012 Feb; 19(2): 258–64PubMedCrossRefGoogle Scholar
  39. 38.
    Reichmann H, Jost WH. Efficacy and tolerability of rasagiline in daily clinical use: a post-marketing observational study in patients with Parkinson’s disease. Eur J Neurol 2010 Sep; 17(9): 1164–71PubMedCrossRefGoogle Scholar
  40. 39.
    Goetz CG, Schwid SR, Eberly SW, et al. Safety of rasagiline in elderly patients with Parkinson disease. Neurology 2006 May; 66(9): 1427–9PubMedCrossRefGoogle Scholar
  41. 40.
    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 Oct; 248(1–2): 78–83PubMedCrossRefGoogle Scholar
  42. 41.
    Teva Pharmaceutical Industries Ltd. Teva announces Health Canada approves Azilect® (rasagiline) for Parkinson’s disease [online]. Available from URL: http://www.tevapharm.com/en-US/Media/News/Pages/2006/1557352. aspx [Accessed 2012 Jan 31]
  43. 42.
    Teva Pharmaceutical Industries Ltd. Teva announces that Azilect® (rasagiline) is approved for marketing in Israel [online]. Available from URL: http://www.tevapharm.com/en-US/Media/News/Pages/2005/1557104.aspx [Accessed 2012 Jan 31]
  44. 43.
    Henchcliffe C, Severt WL. Disease modification in Parkinson’s disease. Drugs Aging 2011; 28(8): 605–15PubMedCrossRefGoogle Scholar
  45. 44.
    Olanow CW, Kieburtz K. Defining disease-modifying therapies for PD: a road map for moving forward. Mov Disord 2010 Sep; 25(12): 1774–9PubMedCrossRefGoogle Scholar
  46. 45.
    National Institute for Health and Clinical Excellence. Parkinson’s disease: diagnosis and management in primary and secondary care (NICE clinical guideline 35). London: NICE, 2006 [online]. Available from URL: http://www.nice.org.uk/nicemedia/live/10984/30088/30088.pdf [Accessed 2011 Jul 27]
  47. 46.
    Oertel WH, Berardelli A, Bloem BR, et al. Early (uncomplicated) Parkinson’s disease. In: Gilhus NE, Barnes MP, Brainin M, editors. European handbook of neurological management. 2nd ed. Oxford: Wiley-Blackwell, 2011; 1: 217–36Google Scholar
  48. 47.
    Scottish Intercollegiate Guidelines Network. Diagnosis and pharmacological management of Parkinson’s disease: a national clinical guideline (SIGN publication no. 113). Edinburgh: SIGN, 2010 JanGoogle Scholar
  49. 48.
    Oertel WH, Berardelli A, Bloem BR, et al. Late (complicated) Parkinson’s disease. In: Gilhus NE, Barnes MP, Brainin M, editors. European handbook of neurological management. 2nd ed. Oxford: Wiley-Blackwell, 2011; 1: 237–67Google Scholar
  50. 49.
    Miyasaki JM, Martin W, Suchowersky O, et al. Practice parameter: initiation of treatment for Parkinson’s disease. An evidence-based review: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2002 Jan; 58(1): 11–7Google Scholar
  51. 50.
    Schapira AH. Treatment options in the modern management of Parkinson disease. Arch Neurol 2007 Aug; 64(8): 1083–8PubMedCrossRefGoogle Scholar
  52. 51.
    Zesiewicz TA, Sullivan KL, Arnulf I, et al. Practice parameter: treatment of nonmotor symptoms of Parkinson disease. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2010 Mar; 74(11): 924–31PubMedCrossRefGoogle Scholar
  53. 52.
    Ahlskog JE, Uitti RJ. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? Neurology 2010 Apr; 74(14): 1143–8PubMedCentralPubMedCrossRefGoogle Scholar
  54. 53.
    Olanow CW, Rascol O. The delayed-start study in Parkinson disease: can’t satisfy everyone [letter]. Neurology 2010 Apr; 74(14): 1149–50PubMedCrossRefGoogle Scholar
  55. 54.
    Ahlskog JE, Uitti RJ. Reply to Drs. Olanow and Rascol [letter]. Neurology 2010 Apr; 74(14): 1151Google Scholar
  56. 55.
    Montgomery Jr EB. The delayed-start study in Parkinson disease: can’t satisfy everyone. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? [letter]. Neurology 2010 Nov; 75(21): 1943; author reply 1944-5Google Scholar
  57. 56.
    Schwarzschild MA. The delayed-start study in Parkinson disease: can’t satisfy everyone. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? [letter]. Neurology 2010 Nov; 75(21): 1943–4; author reply 1944-5Google Scholar
  58. 57.
    Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 2003; 18(7): 738–50CrossRefGoogle Scholar
  59. 58.
    Teva Pharmaceutical Industries Ltd. ADAGIO follow up study: evaluation of the long-term effects of rasagiline in Parkinson’s disease subjects [ClinicalTrials.gov identifier NCT00936676]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ [Accessed 2012 Jan 27]
  60. 59.
    Haycox A, Armand C, Murteira S, et al. Cost effectiveness of rasagiline and pramipexole as treatment strategies in early Parkinson’s disease in the UK setting: an economic Markov model evaluation. Drugs Aging 2009; 26(9): 791–801PubMedCrossRefGoogle Scholar
  61. 60.
    Groenendaal H, Tarrants ML, Armand C. Treatment of advanced Parkinson’s disease in the United States: a cost-utility model. Clin Drug Invest 2010; 30(11): 789–98CrossRefGoogle Scholar
  62. 61.
    Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000 Oct 18; 284(15): 1931–8CrossRefGoogle Scholar
  63. 62.
    Hudry J, Rinne JO, Keränen T, et al. Cost-utility model of rasagiline in the treatment of advanced Parkinson’s disease in Finland. Ann Pharmacother 2006 Apr; 40(4): 651–7PubMedCrossRefGoogle Scholar
  64. 63.
    Liu R, Gao X, Lu Y, et al. Meta-analysis of the relationship between Parkinson disease and melanoma. Neurology 2011 Jun; 76(23): 2002–9PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2012

Authors and Affiliations

  1. 1.AdisMairangi Bay, North Shore 0754, AucklandNew Zealand

Personalised recommendations