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- Oldfield, V., Keating, G.M. & Perry, C.M. Drugs (2007) 67: 1725. doi:10.2165/00003495-200767120-00006
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Rasagiline (Azilect®) is a novel, selective, irreversible second-generation inhibitor of monoamine oxidase type B (MAO-B). It is administered orally once daily and is approved in the US, Canada, Mexico, Israel and the EU for use as monotherapy and as adjunct therapy in the treatment of Parkinson’s disease.
Results of well designed clinical studies indicate that rasagiline is effective as initial monotherapy and improves Parkinson’s symptomatology in patients with early Parkinson’s disease. In addition, when administered in conjunction with levodopa, in patients with moderate to advanced disease and motor fluctuations, rasagiline reduces mean daily ‘off’ time and increases daily ‘on’ time without troublesome dyskinesias, compared with controls. Rasagiline is generally well tolerated as monotherapy and adjunctive therapy and is administered once daily. Thus, rasagiline, administered as a simple and convenient dosage regimen, is a well tolerated and effective option for monotherapy in patients with early Parkinson’s disease and for adjunctive therapy in patients with moderate to advanced disease.
Rasagiline selectively and irreversibly inhibited MAO-B activity in a number of in vitro and in vivo studies. It was 5- to 10-fold more potent than selegiline at inhibiting MAO-B activity in rats. The inhibition of MAO-B activity by rasagiline is thought to lead to an increase in striatal extracellular dopamine levels and may account for the beneficial effect of rasagiline treatment on motor function observed in animal models of Parkinson’s disease.
Rasagiline has demonstrated neuroprotective activity in animal studies and in vitro. Its main metabolite, l-(R)-aminoindan has shown beneficial effects in vitro and in vivo and does not inhibit the anti-apoptotic activity of rasagiline and has no sympathomimetic effects, unlike the major selegiline metabolites, L-amphetamine (L-amfetamine) and L-methamphetamine (L-metamfetamine), which are neurotoxic and inhibit the neuroprotective activity of the parent drug.
In humans, oral rasagiline is rapidly absorbed, reaching a maximum plasma concentration (Cmax) in ≤0.7 hours. Log Cmax was significantly correlated with the percentage of platelet MAO-B inhibition in healthy volunteers. Rasagiline undergoes extensive hepatic metabolism, with less than 1% of the dose being eliminated in the urine unchanged. The main metabolites are l-(R)-aminoindan, 3-hydroxy-N-propargyl-1-aminoindan and 3-hydroxy-1-aminoindan. Cmax and the area under the plasma concentration-time curve increased by 2-fold and 7-fold, respectively, in patients with moderate hepatic impairment (Child-Pugh score 7–9) compared with healthy individuals, following repeat dose administration for 7 days. The pharmacokinetic parameters of rasagiline in patients with mild or moderate renal impairment are similar to those observed in healthy volunteers.
The therapeutic efficacy of oral once-daily rasagiline has been evaluated in three large well designed clinical trials. Patients with early Parkinson’s disease received rasagiline as early initial monotherapy in the TEMPO trial, which was designed to evaluate the efficacy of rasagiline prior to treatment with dopaminergic agents including levodopa. In the PRESTO and LARGO trials, patients with moderate to advanced disease and motor fluctuations received rasagiline as an adjunct to levodopa plus a dopa decarboxylase inhibitor.
In the TEMPO trial, the change from baseline in mean adjusted total Unified Parkinson’s Disease Rating Scale (UPDRS) scores favoured rasagiline 1 or 2 mg/day versus placebo recipients at 26 weeks and early-start rasagiline 1 or 2 mg/day versus delayed-start (by 6 months) rasagiline 2 mg/day at 52 weeks. At 26 weeks, the change from baseline in UPDRS motor, activities of daily living (ADL), tremor and bradykinesia scores also significantly favoured rasagiline recipients, and health-related quality of life (HR-QOL) remained stable with rasagiline. Significantly more rasagiline 1 and 2 mg/day than placebo recipients responded to treatment (experienced a <3-unit increase in total UPDRS score) at 26 weeks. To date, rasagiline therapy has been shown to adequately control Parkinson’s symptoms in the long term (6.5 years) and the beneficial effect of earlyversus delayedstart rasagiline was maintained during this period.
Rasagiline 0.5 and 1 mg/day together with levodopa and other antiparkinsonian therapy significantly decreased the amount of daily ’off time (primary endpoint) compared with placebo in the PRESTO (0.5 and 1 mg/day) and LARGO (1 mg/day) trials. Additionally, compared with placebo, rasagiline recipients had significantly improved Clinical Global Impression (CGI) scores, UPDRS ADL scores during ‘off’ time and UPDRS motor scores during ‘on’ and ‘off time’. Levodopa-responsive symptoms, including tremor, rigidity and bradykinesia, improved with rasagiline, improving ‘on’ time without troublesome dyskinesias and the response to treatment (≥1 hour decrease in mean total daily ‘off’ time) was significantly greater with rasagiline than placebo in the LARGO trial. Rasagiline treatment had no effect on HR-QOL in the more advanced Parkinson’s disease patients in the PRESTO trial.
Rasagiline was generally well tolerated as monotherapy in patients with early Parkinson’s disease. The most frequently occurring adverse events in rasagiline recipients during the first 26 weeks of the TEMPO trial were infection and headache. During the long-term TEMPO extension (up to 6.5 years) rasagiline was well tolerated with the most common adverse events reported being infection and accidental injury.
Rasagiline was also generally well tolerated when added to other antiparkinsonian medication in patients with moderate to advanced disease and motor fluctuations, with the most commonly occurring adverse events being dopaminergic related. The incidence of dopaminergic adverse events was similar with rasagiline and placebo in the LARGO trial, but in the PRESTO trial rasagiline recipients reported a significantly greater incidence of weight loss, vomiting, anorexia, balance difficulty and dyskinesias. Depression occurred significantly less frequently with rasagiline than with placebo in the PRESTO trial.
Serious adverse events with rasagiline were infrequent and rasagiline treatment had little or no effect on ECG recordings, blood pressure, heart rate or laboratory measurements. No increase in sensitivity to tyramine was observed following a tyramine challenge performed in subpopulations of patients at the end of the TEMPO and PRESTO trials. All three trials were without dietary tyramine restrictions and no cases of hypertensive crisis were reported. Discontinuation rates due to adverse events were low.
Parkinson’s disease is a progressive neurodegenerative disease that is characterised by the symptoms of resting tremor, rigidity, bradykinesia and postural instability.[1,2] After Alzheimer’s disease, it is the second most common neurodegenerative disease; Parkinson’s disease affects approximately 1–2% of the European population over the age of 65 years, and the prevalence increases to 2–3% in those aged 85–89 years.[1,3] In the US, the prevalence of Parkinson’s disease was estimated to be 1 200 000 in 2005 and is predicted to reach 1 860 000 in 2015. Similarly, an increase in the prevalence of Parkinson’s disease, from 240 000 in 2005 to 370 000 in 2015, has been predicted in the UK.
Although several contributing factors have been identified, the underlying aetiology of Parkinson’s disease remains unknown. The pathogenesis of the disease is thought to involve necrosis and/or apoptosis of dopaminergic neurons,[5,6] and clinical signs of Parkinson’s disease appear when approximately 80% of striatal dopamine and 50% of nigral neurons are lost. Current pharmacological, surgical and rehabilitative therapeutic approaches are palliative only and have not been shown to halt or slow disease progression.
Treatment of Parkinson’s disease is usually initiated when functional disability or an impact on quality of life is evident and is individualised according to the patient’s symptoms. There is, however, a growing trend to initiate treatment at an early stage of the disease. The definition of functional impairment (FI) is highly variable and dependent on individual patient characteristics, including age and vocation. Levodopa, the precursor of dopamine, forms the backbone of therapy for Parkinson’s disease (although not at early stages). However, within 5 years of starting levodopa treatment, up to 50% of patients experience levodopa-related motor fluctuations such as ‘wearing-off’ and ‘on-off’ effect. Other symptoms that are not adequately controlled by levodopa, such as freezing of gait, autonomic dysfunction and dementia, develop as the disease progresses.
Other antiparkinsonian agents, such as dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors, are used as monotherapy as alternatives to levodopa and may be used instead of, or in conjunction with, levodopa in patients with moderate to advanced disease.[2,9] Catechol-O-methyl transferase (COMT) inhibitors are frequently administered with levodopa to alleviate levodopa-related motor fluctuations.
MAO-B is the major enzyme responsible for the metabolism of dopamine in the human brain and inhibition of its activity helps to conserve the supply of dopamine. Until recently, selegiline was the only approved MAO-B inhibitor for use in the treatment of Parkinson’s disease and, in the US, was only approved as adjunctive therapy to levodopa.
Rasagiline (Azilect®)1 is a novel, selective, irreversible, second generation inhibitor of MAO-B that has recently been approved in the US, Canada, Mexico, Israel and the EU for use as initial monotherapy in early Parkinson’s disease and as adjunctive therapy to levodopa in moderate to advanced Parkinson’s disease.[11,12] This article reviews the use of rasagiline as monotherapy or as adjunctive therapy in combination with levodopa in patients with Parkinson’s disease. The pharmacology and clinical profile of rasagiline have been reviewed previously in Drugs & Aging.
2. Pharmacodynamic Properties
2.1 Mechanism of Action
Rasagiline selectively inhibited MAO-B in a number of in vitro and in vivo[14,16–23] studies (table I). Rasagiline was 5- to 10-fold more potent (p < 0.05) than selegiline at inhibiting MAO-B activity in vivo (table I). With single doses of rasagiline 1, 2, 5 or 10mg, maximal inhibition of platelet MAO-B activity (a marker for brain MAO-B activity) was observed 1 hour after administration in healthy volunteers (MAO-B activity inhibited by approximately 35%, 55%, 79% and 99%, respectively; all p < 0.05 vs placebo). With repeated administration of rasagiline 2 mg/day, almost complete (>99%) MAO-B inhibition was achieved on day 6. In this study, the percentage of MAO-B inhibition correlated with the log of the maximum plasma concentration (Cmax) of rasagiline (correlation coefficient = 0.79, p < 0.001) [section 3]. In human brain tissue in vitro, the rasagiline concentration inhibiting MAO-B activity by 50% (IC50) was 14 nmol/L, compared with 710 nmol/L for inhibition of MAO-A activity; corresponding IC50 values for inhibition of MAO-B and MAO-A by selegiline were 6.8 and 1700 nmol/L, respectively.
The inhibitory activity of rasagiline is irreversible.[15,17] A decrease in MAO-B activity was observed in the thalamus and basal ganglia immediately after the last dose of rasagiline in healthy volunteers who received rasagiline 1 mg/day for 10 days and recovery of MAO-B activity in these areas occurred gradually over 6 weeks, consistent with reports that the half-life for de novo synthesis of MAO-B is 40 days.[15,46] In another study in healthy human volunteers, maximum inhibition of MAO-B activity was maintained for at least 48 hours following administration of a single dose of rasagiline 1–10mg and a significant difference in MAO-B inhibition was evident with rasagiline compared with placebo 7 days after administration of rasagiline 10mg (p < 0.05). Platelet MAO-B activity returned to normal 14 days after rasagiline administration in this study.
Inhibition of MAO-B activity by rasagiline is thought to cause an increase in extracellular striatal dopamine levels; administration of rasagiline 0.5–5 mg/kg/day for 21 days produced significant increases in dopamine levels in extracellular striatal rat and monkey tissue (table I). Corresponding decreases in the levels of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), observed in some studies,[18,24] suggest that the increase in dopamine levels is the result of inhibition of MAO metabolism of dopamine by rasagiline. Additional mechanisms of action have been suggested, including accumulation of endogenous beta-phenylethylamine. Increased dopamine levels may account for the beneficial effects of rasagiline treatment on motor function observed in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of Parkinson’s disease in the marmoset; rasagiline treatment attenuated the MPTP-induced decline in spontaneous locomotor activity and increase in Parkinsonian signs (according to a non-human primate Parkinsonian rating scale).
2.2 Neuroprotective Effects
Rasagiline has demonstrated neuroprotective properties in vivo in animal models of neuronal degeneration[28,40,41,48] and in response to focal ischemia and head injury (table I). It has also demonstrated neuroprotective activity in vitro in fetal rat[26,27] and human ventral mesencephalon and in response to neurotoxins[21,35,36,38] and oxygen/glucose, serum or nerve growth factor deprivation[30–34] (table I). The neuroprotective effect of rasagiline is independent of its MAO-B inhibitory activity.[34–36] Indeed, some of the neuroprotective effects of rasagiline have been seen in cell lines and primary neurones that express only the MAO-A isoenzyme.[35,37,49–51] Furthermore, the (S)-enantiomer of rasagiline, which lacks MAO-inhibitory activity, has also shown protective effects in vitro and in vivo.[29,35,39,52,53] Thus, the neuroprotective effects of rasagiline cannot be attributed in the main to its inhibition of MAO-B. Structure-activity studies have shown that this activity is associated with the propargyl moiety of rasagiline.
The neuroprotective activity of rasagiline may be due to its ability to inhibit apoptosis, which has been demonstrated in various in vitro studies,[30–36,38] and is thought to be the result of inhibition of the apoptotic cascade initiated by mitochondria involving interaction with protein kinase C isozymes and upregulation of anti-apoptotic Bcl-2 family proteins (table I).[32,34,35,37,43–45]
Unlike the major selegiline metabolites, L-amphetamine (L-amfetamine) and L-methamphetamine (L-metamfetamine), which are neurotoxic and inhibit the neuroprotective activity of the parent drug, the major metabolite of rasagiline, 1-(R)-aminoindan, does not inhibit the anti-apoptotic activity of rasagiline and has no sympathomimetic activity.[33,55] 1-(R)-aminoindan did not potentiate oxygen-glucose deprivation-induced cell death in rat nerve growth factor-differentiated phaeochromocytoma (PC12) cells, compared with L-methamphetamine, which increased cell death by ≈70%. In rats, L-methamphetamine was associated with dramatic reductions in mean arterial pressure and carotid blood flow and an increase in carotid vascular resistance (all p < 0.05 vs baseline), whereas 1-(R)-aminoindan induced much milder changes in these parameters. 1-(R)-aminoindan has also demonstrated neuroprotective activity in vitro and, although it is not a MAO inhibitor, it was more active than rasagiline in preventing α-methyl-p-tyrosine-induced hypokinesia in hypoxia-lesioned adult rats.
3. Pharmacokinetic Properties
The pharmacokinetic data presented in this section have been sourced from studies in healthy volunteers and patients with Parkinson’s disease[16,56] receiving oral rasagiline at dosages of up to 4 mg/day. Additional data have been sourced from the prescribing information.[11,12]
3.1 Absorption and Distribution
Rasagiline reached a Cmax in a time (tmax) of ≤0.7 hours (table II) following oral administration of single or multiple 0.5–2mg doses in healthy volunteers and in patients with Parkinson’s disease.[16,17] Rapid absorption of rasagiline is consistent with the observation that MAO-B inhibition occurs within 1 hour of administration of rasagiline, since log Cmax correlated with the percentage of platelet MAO-B inhibition in healthy volunteers (section 2.1). The absolute bioavailability following a single dose of oral rasagiline is ≈36%.
The area under the plasma concentration-time curve (AUC) was significantly higher (p < 0.001) after administration of rasagiline 2 mg/day for 10 days than after administration of a single 2mg dose (table II). This increase may reflect the binding of rasagiline to MAO-B sites; after saturation of MAO-B sites, rasagiline concentrations should remain constant with repeat administration. AUC and Cmax also increased linearly in proportion to the rasagiline dosage over the range 0.5–10 mg/day.[16,17,56] Cmax and the AUC increased by 2-fold and 7-fold, respectively, in patients with moderate hepatic impairment (Child-Pugh score 7–9) compared with healthy individuals, following repeat dose administration for 7 days. Rasagiline is contraindicated in patients with severe hepatic insufficiency and use in patients with moderate hepatic insufficiency should be avoided.[11,12]
The mean volume of distribution (Vd) ranged from 182L for oral rasagiline 4 mg/day in patients with Parkinson’s disease to 243L for intravenous rasagiline. A steady-state Vd of 87L has also been reported. Rasagiline is 60–70% plasma protein-bound after a single oral dose.
3.2 Metabolism and Elimination
Rasagiline is metabolised in the liver, where it undergoes nearly complete biotransformation to yield the metabolites 1-(R)-aminoindan (the major active metabolite [section 2]), 3-hydroxy-N-propargyl-1 aminoindan and 3-hydroxy-1-aminoindan.[11,12] 1-(R)-aminoindan is present in plasma at a lower concentration than the parent drug and the Cmax and AUC for 1-(R)-aminoindan increase proportionally when the rasagiline dosage increases.[16,17,56] Unlike selegiline, rasagiline is not metabolised to amphetamine or amphetamine derivatives.
The two main pathways of rasagiline metabolism, N-dealkylation and hydroxylation, are dependent on the cytochrome P450 (CYP) system.[11,12] In particular, the major isoenzyme involved in rasagiline metabolism is CYP1A2; therefore, coadministration of rasagiline with a CYP1A2 inhibitor, such as ciprofloxacin, is contraindicated in Europe. In the US, the dosage of rasagiline should be reduced to 0.5mg daily in patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors.  In vitro studies showed that rasagiline did not inhibit CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 or CYP4A.
The terminal half-life (t1/2) of rasagiline is independent of the dose and ranged from 0.6 to 2 hours following administration of rasagiline 0.5–2mg (route of administration not specified). Following oral administration of rasagiline 2 mg/day for 10 days in healthy volunteers, the mean t1/2 was 2.06 hours (table II). The mean steady-state t1/2 of rasagiline is 3 hours in patients with Parkinson’s disease.
Elimination of rasagiline is primarily via urine, where less than 1% of the rasagiline dose is excreted unchanged. Following oral administration of 14C-labelled rasagiline, 84.4% of the dose was recovered over a period of 38 days: 62.6% was eliminated via urine and 21.8% via faeces. The renal clearance (CLR) of rasagiline decreases with repeat administration; the CLR of rasagiline 2 mg/day at day 10 was significantly lower than at day 1 in healthy volunteers (p < 0.05) [table II]. The pharmacokinetic parameters of rasagiline in patients with mild or moderate renal impairment are similar to those observed in healthy volunteers; dosage modification is therefore not required for such patients.
4. Therapeutic Efficacy
Three large (n > 400 per study) randomised, double-blind, parallel-group, multicentre clinical trials have evaluated the efficacy of once daily oral rasagiline in patients with early Parkinson’s disease who received rasagiline as their first treatment (section 4.1) and in patients with moderate to advanced disease and motor fluctuations who received rasagiline as adjunctive therapy (section 4.2).[59,60]
Preliminary evidence for the efficacy of rasagiline in the treatment of Parkinson’s disease was found in two small, randomised, double-blind, parallel-group, placebo-controlled, multicentre trials in patients with early disease who received rasagiline 1–4 mg/day as monotherapy (n = 56) and in patients with moderate to advanced disease who received rasagiline 0.5–2 mg/day in addition to levodopa (n = 70). The results of these two published trials are not discussed further.
4.1 As Monotherapy in Patients with Early Parkinson’s Disease
The efficacy of rasagiline monotherapy, administered once daily, was evaluated for 6 months in patients with early Parkinson’s disease in the TEMPO (TVP-1012 in Early Monotherapy for Parkinson disease Outpatients) trial. This trial was designed to evaluate the efficacy of rasagiline prior to treatment with dopaminergic agents including levodopa. There were no dietary tyramine restrictions. This trial also assessed the effect of early- versus delayed-start rasagiline monotherapy after 12 months of treatment and results are available for up to 6.5 years of treatment in the ongoing open-label follow-up period.[62,63]
Patients enrolled in the TEMPO trial (n = 404) were aged >35 years with at least two of the cardinal signs of Parkinson’s disease and maximum disease severity of Hoehn and Yahr stage III. In the initial double-blind, placebo-controlled phase, patients were randomised to receive rasagiline 1 or 2 mg/day or placebo for 26 weeks. At 26 weeks, placebo recipients were switched to rasagiline 2 mg/day (delayed-start rasagiline) while other rasagiline recipients continued their originally randomised treatment for another 26 weeks in the second, double-blind treatment phase. During the subsequent, open-label, follow-up period, all patients were switched to rasagiline 1 mg/day. Additional antiparkinsonian medication (levodopa and/or dopamine agonists) was added as required. Long-term results following administration of rasagiline for up to 6.5 years (data available as abstracts and posters only) have been presented for a single cohort of all patients treated with rasagiline at any time and for the early- versus delayed-start treatment groups.
The primary efficacy outcome of the TEMPO trial was the change from baseline in the total Unified Parkinson’s Disease Rating Scale (UPDRS) score at 26 and 52 weeks. Results for the initial, placebo-controlled phase were reported for the intention-to-treat (ITT) population which included all randomised patients. Results for the second phase were reported for patients with at least one post-randomisation measurement, using last observation carried forward (LOCF) analysis where data were missing or incomplete. The adjusted effect size was the between-group difference in the mean total UPDRS score change from baseline for rasagiline 1 or 2 mg/day versus placebo at 26 weeks (n = 404) and versus delayed-start rasagiline at 52 weeks (n = 371), adjusted for baseline UPDRS score, centre, treatment and centre-treatment interaction. During the open-label follow-up period, UPDRS assessments were conducted every 3 months and long-term results were reported for all patients treated with rasagiline during any phase of the trial (n = 398) and for the ITT population of patients (n = 404) in the ongoing phase of the trial only.
Secondary endpoints evaluated in the first and second double-blind phases of the trial included changes in the mental, activities of daily living (ADL) and motor UPDRS subscale scores; symptom-based tremor, rigidity, bradykinesia and postural instability/gait disorder UPDRS subscores; changes in the Parkinson’s disease quality-of-life (PD-QUALIF) scale; and the proportion of responders to treatment (those patients who experienced a worsening in the total UPDRS of <3 units from baseline to 26 weeks or a worsening of <4 units over the 12-month study period).
Baseline total UPDRS scores were similar for the rasagiline 1 and 2 mg/day and placebo treatment groups (24.7, 25.9 and 24.5, respectively). UPDRS motor, ADL, mental and bradykinesia subscale scores and PD-QUALIF scores were also similar between treatment groups at baseline (17.6–18, 5.9–6.7, 0.8–1.2, 7.8–8.3 and 26.9–30.2, respectively).
The change from baseline in UPDRS motor, ADL, tremor and bradykinesia subscores also significantly favoured rasagiline.[58,61] At 26 weeks, the change from baseline in the mean adjusted UPDRS motor and ADL scores with rasagiline 1 and 2 mg/day indicated that worsening of symptoms was significantly less with rasagiline than with placebo; between-group differences are shown in figure 1 and changes from baseline are shown in table III(p ≤ 0.005 for each comparison). The between-group difference in the change from baseline in the mean adjusted bradykinesia score at 26 weeks was −1.51 (95% CI −2.19, −0.82 ) for rasagiline 1 mg/day versus placebo and −0.77 (95% CI −1.47, −0.08) for rasagiline 2 mg/day versus placebo (p < 0.001 for each comparison). The between-group difference in the change from baseline in the mean adjusted tremor score at 26 weeks was −0.63 (95% CI −1.03, −0.23) for rasagiline 1 mg/day versus placebo (p < 0.05) and −0.38 (95% CI −0.78, 0.02) for rasagiline 2 mg/day versus placebo. Treatment with rasagiline had no significant effect on the UPDRS mental score (figure 1).[58,61] At 52 weeks, there was a significant between-group difference in the change from baseline in the mean adjusted UPDRS ADL score for rasagiline 2 mg/day compared with delayed-start rasagiline 2 mg/day (−0.96; p = 0.005; figure 1).
In a post hoc analysis performed on the 26-week placebo-controlled phase of the TEMPO study, in which the size of effect of treatment with rasagiline 1 mg/day was assessed in relation to the severity of Parkinson’s disease at baseline, the symptomatic benefits of treatment compared with baseline appeared to be more marked in patients with more pronounced symptoms at baseline (reported in a poster). Compared with placebo, rasagiline produced improvements of >6 UPDRS units in patients with Parkinson’s disease of greater severity at baseline (baseline total UPDRS score >31) over a period of 6 months.
Health-related quality of life (HR-QOL), as measured by the PD-QUALIF scale, stabilised with rasagiline monotherapy versus placebo over the initial 26-week study period; the between-group difference in the change from baseline in the PD-QUALIF score at 26 weeks with rasagiline 1 and 2 mg/day relative to placebo was −2.91 (95% CI −5.19, −0.64; p = 0.01) and −2.74 (95% CI −5.02, −0.45; p = 0.02).[58,68] The duration of rasagiline treatment did not affect HR-QOL; at the end of the 52-week active-treatment phase, there were no differences between early- and delayed-start rasagiline in the change from baseline in the PD-QUALIF score. The improvement in HR-QOL in the entire study group in the TEMPO trial was shown to be independent of age (age <65 years vs ≥65 years) in a post hoc analysis reported in a poster.
Significantly more patients who received rasagiline 1 and 2 mg/day as monotherapy compared with placebo recipients responded to treatment (a <3-unit worsening in total UPDRS score) after 26 weeks (66% and 67% vs 49%; p ≤ 0.004). The proportion of responders was also significantly higher following treatment with rasagiline 2 mg/day for 52 weeks compared with delayed-start rasagiline (64% vs 52%; p = 0.04). There was no significant difference in the response rate between the rasagiline 1 mg/day and delayed-start rasagiline treatment groups at 52 weeks (53% vs 52%).
In the long-term extension phase of 6.5 years, the proportions of patients who were maintained on rasagiline and did not require additional dopaminergic therapy at 2 and 6 years were 45% (121 of 266 patients) and 17% (45 of 266).
Patients who received early-start rasagiline had a 16% smaller increase from baseline in total UPDRS score (indicating less functional decline) compared with delayed-start rasagiline recipients (p = 0.006) at 6 months. The beneficial effect of early- versus delayed-start rasagiline was maintained during the long-term (6-year) follow-up period, suggesting that early use of rasagiline may delay symptom progression. A similar proportion of patients in the early- and delayed-start treatment groups received levodopa and/or dopamine agonists (66% and 70%); the median time from baseline to the addition of levodopa and/or dopamine agonists was similar in each treatment group (1.5 and 1.8 years).
4.2 As Adjunctive Therapy in Patients with Moderate to Advanced Parkinson’s Disease and Motor Fluctuations
The primary efficacy variable in both trials was the change from baseline in mean total daily ‘off’ time as measured by patients’ home diaries.[59,60] Secondary analyses, listed in a pre-specified order used for the purposes of statistical analysis, included the Clinical Global Impression (CGI) score[59,60] and the change from baseline in the UPDRS ADL score during ‘off’ time,[59,60] the UPDRS motor score during ‘on’ time[59,60] and the PD-QUALIF score (PRESTO trial only). Statistical analysis was conducted on the ITT population, including all patients with at least one post-randomisation measurement or diary entry for that endpoint.[59,60] For secondary endpoints in the PRESTO study and for endpoints that were not derived from diaries in the LARGO study, LOCF analysis was used where data were missing or incomplete.
Two ancillary studies conducted within the LARGO trial framework (available as posters and abstracts) assessed the effect of rasagiline on freezing of gait (n = 454; 10 weeks’ follow-up) and severity of motor symptoms during ‘off’ time (n = 105; 18 weeks’ follow-up). Additional 18-week LARGO trial results and 26-week PRESTO trial results have also been reported.
At baseline, mean daily ‘off’ time and mean daily levodopa dosage were similar across treatment arms in both trials.[59,60] Patients in the LARGO trial had 5.55–5.60 hours of mean daily ‘off’ time and were receiving levodopa 697–722 mg/day at baseline. In the PRESTO trial, patients had 6.0–6.3 hours of mean daily ‘off’ time and were receiving levodopa 750–821 mg/day at baseline.
Rasagiline significantly improved motor fluctuations in patients with moderate to advanced Parkinson’s disease already optimised on levodopa and other therapies.[59,60] Although the PRESTO and LARGO trials were conducted in different geographical locations, rasagiline 1 mg/day showed comparable efficacy and consistent treatment benefits in patients with moderate to advanced Parkinson’s disease in these two studies. Adjunctive therapy with rasagiline 0.5 or 1 mg/day significantly decreased the amount of daily ‘off’ time compared with placebo (between-group differences are shown in table IV).[59,60] Mean adjusted total daily ‘off’ time was reduced from baseline by 1.18–1.85 hours with rasagiline 1 mg/day,[59,60] 1.41 hours with rasagiline 0.5 mg/day, by 1.20 hours with entacapone and by 0.40 and 0.91 hours with placebo.
Compared with placebo, rasagiline significantly increased daily ‘on’ time without troublesome dyskinesia, improved CGI scores and decreased UPDRS ADL scores during ‘off’ time (table IV).[59,60] Rasagiline treatment did not affect HR-QOL in the more advanced patients in the PRESTO trial; the change from baseline in the PD-QUALIF score with rasagiline 0.5 and 1 mg/day was not significantly different from that observed with placebo (table IV). In the LARGO trial, entacapone also significantly improved daily ‘off’ time, daily ‘on’ time without dyskinesia and UPDRS ADL scores relative to placebo (table IV).
Rasagiline also significantly improved motor symptoms during both ‘on’ and ‘off’ time;[59,60,71] the change from baseline in UPDRS motor scores during ‘on’ and ‘off’ time significantly favoured rasagiline compared with placebo.[59,60,71] The change in UPDRS motor score during ‘on’ time was significantly greater with rasagiline and entacapone compared with placebo (table IV).[59,60] The UPDRS motor score during ‘off’ time was 5.64 units lower with rasagiline than placebo in a substudy of LARGO (p = 0.013); the effect of entacapone was not significant versus placebo in this substudy.[71,76]
Levodopa-responsive symptoms, including tremor, rigidity and bradykinesia, improved with rasagiline according to post hoc analysis in the LARGO trial and a pre-specified analysis in an ancillary study to the LARGO trial. Compared with placebo, significant improvements in UPDRS tremor, rigidity and bradykinesia subscores were reported with rasagiline and entacapone (table V). Tremor, rigidity and bradykinesia also improved in the PRESTO trial. Within the LARGO trial, the change from baseline in the UPDRS freezing subscale score for patients who displayed freezing when walking at baseline (n = 278) significantly favoured rasagiline 1 mg/day versus placebo recipients (between-group difference -0.16; p = 0.045). In addition, compared with placebo, the UPDRS postural instability gait difficulty subscore was significantly improved in recipients of rasagiline 1 mg/day (between-group difference = −0.31; p = 0.034) but was not improved in entacapone recipients. In an ancillary study of the LARGO trial, patients who received rasagiline 1 mg/day (n = 150) for 10 weeks experienced a significantly greater decrease from baseline in the score for the Freezing of Gait Questionnaire compared with placebo recipients (n = 154) [−1.17 vs −0.48; p = 0.045]. The changes from baseline in the UPDRS tremor, rigidity and bradykinesia subscale scores at 18 weeks in the LARGO trial also significantly favoured rasagiline 1 mg/day as well as entacapone versus placebo recipients; between-group differences for rasagiline versus placebo were −0.6, −0.6 and −1.36, respectively (p ≤ 0.0065 for each comparison).
Response to treatment, defined as a ≥1-hour decrease in mean total daily ‘off’ time, was significantly greater with rasagiline than placebo in the LARGO trial; 113 of 222 (51%) patients in the rasagiline treatment group were responders compared with 70 of 218 (32%) in the placebo group (p < 0.0001). In the entacapone group, 99 of 218 (45%) patients were responders (p = 0.0019 vs placebo). The response to treatment was not affected by age or concomitant use of dopamine agonists. Rasagiline and entacapone recipients in this study also had a significant reduction in levodopa dosage (−24 and −19 mg/day vs +5 mg/day with placebo; p = 0.0003) [the levodopa dosage could be adjusted only during the first 6 weeks of the LARGO trial].
Improvements in motor function with rasagiline were similar in patients already optimised on levodopa and other concomitant Parkinson’s disease therapy and patients who were not receiving concomitant therapy, according to subgroup analyses of the LARGO and PRESTO trials. Entacapone recipients in the LARGO trial also experienced improvements in motor function either with or without concomitant dopamine agonist therapy, with the exception of changes in CGI and UPDRS ADL scores during ‘off’ time, which were similar to those in placebo recipients.
As a large proportion of patients with Parkinson’s disease are elderly, pooled data from the subgroup of patients aged ≥70 years who participated in the PRESTO and LARGO trials were analysed to assess treatment efficacy in these patients compared with that in younger patients. Adjunctive rasagiline treatment 1 mg/day was shown to be effective in patients in this older patient population with the efficacy of the drug unaffected by the age of the patient. Another analysis of pooled data from the PRESTO and LARGO studies showed that high-level responses to adjunctive rasagiline therapy 1 mg/day were achieved in levodopa-treated patients with varying degrees of disease severity at baseline, with no between-group differences in responses evident. High-level responses were defined as the highest quartile of responders in each group (reduction in ‘off’ time of >2.56 hours or a >46% reduction in ‘off’ time). Moreover, patients with Parkinson’s disease of moderate severity (as defined by two criteria: on levodopa only, mild fluctuations) with motor fluctuations at baseline were shown to have reductions in daily ‘off’ time and improvements in various global measures after treatment with adjunctive rasagiline 1 mg/day in a post hoc analysis of data from the PRESTO and LARGO studies.
Rasagiline tolerability was assessed during clinical trials of oral rasagiline 1 or 2 mg/day as monotherapy in patients with early Parkinson’s disease (the TEMPO trial)[58,61,62] and rasagiline 0.5 or 1 mg/day in conjunction with levodopa in patients with moderate to advanced disease (the PRESTO and LARGO trials)[59,60] [see sections 4.1 and 4.2 for trial details]. Additional tolerability data were obtained from retrospective analyses of data from the studies and other reports, some of which are abstracts and posters.[74,79,82–90]
Rasagiline was generally well tolerated by elderly (aged ≥70 years) patients when administered as monotherapy or in conjunction with levodopa.[59,79,82] Regardless of treatment with rasagiline or placebo, elderly (aged ≥70 years) patients experienced a significantly higher incidence of serious adverse events in the TEMPO and PRESTO trials (p ≤ 0.04), symptomatic orthostatic hypotension in the TEMPO trial (p = 0.01) and hallucinations in the PRESTO trial (p = 0.01) than patients aged <70 years. Patients aged <70 and ≥70 years reported similar incidences of total adverse events, dyskinesias and confusion in the PRESTO and TEMPO trials and dopaminergic adverse events in the LARGO trial.
Rasagiline was generally associated with low discontinuation rates due to adverse events when administered as monotherapy or as adjunctive therapy. Over 6.5 years, 45 of 398 (11.3%) of patients withdrew from the TEMPO trial because of adverse events.
Serious adverse events with rasagiline were also infrequent, occurring in 5–12% of rasagiline 0.5–2 mg/day recipients and in 3–9% of placebo recipients in all three trials.[58–60] The most common serious adverse events occurring in any treatment group (including placebo) in the PRESTO trial were related to accidental injury (n = 6), arthritis, worsening Parkinson’s disease, melanoma, stroke and urinary tract infection (n = 3 each). Data from a clinical screening programme that was implemented in ongoing trials following the occurrence of some cases of melanoma suggest that Parkinson’s disease patients have an increased risk for melanoma. Epidemiological studies have also indicated that there is a higher incidence of Parkinson’s disease among patients with melanoma than the general population.[92–97]
Rasagiline treatment had no clinical effect on ECG recordings, blood pressure, heart rate or laboratory measurements.[58–60,84] In the PRESTO trial, a greater number of patients receiving rasagiline 0.5 mg/day than placebo had low standing systolic (20 vs 8mm Hg) or diastolic (9 vs 1mm Hg) blood pressure (p < 0.05); no differences were observed between the rasagiline 1 mg/day and placebo treatment groups.
No increase in sensitivity to tyramine was observed in six healthy adult volunteers who received rasagiline 1 mg/day for 10 days. Furthermore, sensitivity to tyramine increased only slightly in six volunteers who received rasagiline 2 mg/day for 10 days; this change in sensitivity to tyramine was similar to that seen with selegiline 10 mg/day. Rasagiline did not interact with tyramine in substudies of the TEMPO[86,87] and PRESTO[87,88] trials. A single dose of 50 or 75mg of tyramine hydrochloride was administered to 55 patients on the last day of the placebo-controlled phase of the TEMPO trial[86,87] and 55 patients who completed the PRESTO trial.[87,88] None of the patients in the TEMPO substudy experienced a tyramine reaction (defined as an increase in systolic blood pressure of >30mm Hg sustained for ≥10 minutes, bradycardia [heart rate <40 beats per minute] or significant ECG changes).[86,87] Four of the patients in the PRESTO substudy had increases in systolic blood pressure of≥30 mmHg for 10 minutes on three consecutive measurements; three patients had received rasagiline 0.5 mg/day (none had received rasagiline 1 mg/day) and one patient had received placebo. The pattern of systolic blood pressure elevation in two of the three rasagiline patients was atypical for a tyramine response and none of the four patients demonstrated clinically significant ECG changes, reflex bradycardia or adverse symptoms associated with a tyramine response. Accordingly, the study investigators reported that rasagiline 1 mg/day can be taken with or without food and no dietary tyramine restrictions are needed.[84,87] Of note, all three phase III trials were conducted without dietary tyramine restriction and no cases of hypertensive crisis were reported. Measurements of blood pressure taken before and after the main meal showed no significant between-group differences in the PRESTO trial.
There was no evidence of unexpected adverse events or serotonin toxicity in the records of 316 patients with Parkinson’s disease who received rasagiline (dosage range 0.5 to 10 mg/day) and concomitant antidepressants (e.g. tricyclics, selective serotonin reuptake inhibitors [SSRIs]) [median treatment time 316 days] in several controlled clinical trials in a retrospective analysis. Moreover, there was no increase in the rate of study termination due to adverse events in this group of patients. In addition, no deleterious clinical interactions between rasagiline and SSRIs were identified among 77 patients in the PRESTO trial, according to preliminary results of a safety substudy. Although the patients receiving concomitant SSRIs experienced a numerically higher incidence of vomiting than patients who did not receive SSRIs (5% vs 1%; p-value not reported), there were no other notable between-group differences in the incidence of adverse events.
6. Dosage and Administration
Rasagiline 1mg tablets are approved in Europe for use in the treatment of idiopathic Parkinson’s disease as initial monotherapy or as an adjunct to levodopa in patients with end-of-dose motor fluctuations. The recommended dosage is 1mg once daily with or without levodopa in adults aged ≥18 years. In the US, the recommended dosage of rasagiline monotherapy is 1mg once daily. As adjunctive therapy, the recommended initial dosage is 0.5mg once daily; the dose may be increased to 1mg once daily if a sufficient clinical response is not achieved.
Because of the route of metabolism (section 3.2), rasagiline is contraindicated in patients with severe hepatic insufficiency, and should be avoided in patients with moderate hepatic impairment. According to the US prescribing information, the dosage of rasagiline for patients with mild hepatic impairment is 0.5mg once daily; patients with moderate or severe hepatic impairment should not be treated with rasagiline. Local prescribing information should be consulted for information about other contraindications, precautions and recommended dosages for special populations.
There are several known interactions between nonselective MAO inhibitors and other drugs. Consequently, the following recommendations apply to the use of rasagiline, according to the European prescribing information. The concomitant use of rasagiline and other MAO inhibitors or pethidine is contraindicated. In addition, the concomitant use of rasagiline and dextromethorphan or sympathomimetics (e.g. decongestants containing ephedrine or pseudoephedrine) is not recommended, and antidepressants (e.g. SSRIs, tricyclic/tetracyclic antidepressants, MAO inhibitors) or potent CYP1A2 inhibitors (e.g. ciprofloxacin; see also section 3.2) should be administered with rasagiline with caution. In addition, the use of fluoxetine or fluvoxamine with rasagiline should be avoided. In the US prescribing information it is recommended that the dosage of rasagiline should be reduced to 0.5mg once daily in patients receiving concomitant ciprofloxacin or other CYP1A2 inhibitors.
7. Place of Rasagiline in the Management of Parkinson’s Disease
Parkinson’s disease is a neurodegenerative disease that occurs commonly in most countries worldwide. It is increasingly common in the elderly, and studies have shown that it is slightly more prevalent in men than in women. Young-onset Parkinson’s disease occurs in people aged <40 years and accounts for approximately 5% of patients with the disease.
Treatment of Parkinson’s disease is complex because of the progressive nature of the disease; worsening parkinsonian symptoms eventually necessitate treatment initiation. The choice of therapy is individualised according to the degree of functional disability that the patient experiences as a result of the disease. Patient age and the tolerability of current medication should also be considered before selecting an appropriate treatment. There is a growing trend to treat Parkinson’s disease at an early stage. A wide range of pharmacological treatment options are available for use at different stages of the disease and surgery and rehabilitation are also options for treatment, although the efficacy of these interventions is still being investigated. The primary goals of treatment for all patients, regardless of the severity of their symptoms, are to target the most disabling symptoms and, if possible, to slow the progression of the disease.
Although patients at all stages of the disease usually experience clinically meaningful benefit from levodopa treatment,[2,7,9] over time the quality of the therapeutic response to levodopa deteriorates and patients develop disabling motor fluctuations (including the ‘wearing-off’ effect and the ‘on-off’ phenomenon), dyskinesias, confusion and hallucinations.[9,98] After 5 years of levodopa treatment, 25–50% of patients experience motor fluctuations; in young-onset patients the prevalence increases to >90%.
Therefore, the decision about when to initiate levodopa therapy involves consideration of the need for rapid symptomatic relief versus the possibility of delaying levodopa treatment to postpone the development of motor complications and other debilitating levodopa-related effects. Treatment with other agents, such as MAO-inhibitors or dopamine agonists, may be initiated as part of a levodopa-sparing strategy.[2,7,9]
In patients with more advanced disease who experience levodopa-related motor fluctuations, dopamine agonists or COMT inhibitors may be added to levodopa treatment to reduce ‘off’ time.[2,98] The patient’s daily dosing regimen becomes more complex with the adjunctive use of these agents, many of which are administered at least twice daily and require individual dosage titration or adjustment of the levodopa dosage. Although selegiline is also indicated for use in conjunction with levodopa, various evidence-based treatment reviews have concluded that there is insufficient evidence to recommend it for the purpose of alleviating levodopa-related motor complications.[98,100,101]
In the EU and the US, rasagiline is indicated as monotherapy or in conjunction with levodopa in patients with Parkinson’s disease (section 6).[11,12] In randomised clinical trials, rasagiline monotherapy had a significant effect on Parkinson’s symptomatology in patients with early Parkinson’s disease compared with placebo (section 4.1)[58,61] and this benefit was maintained in the long term thereby establishing it as a useful option for initial symptomatic monotherapy as part of a levodopa-sparing treatment strategy. Recent evidence-based reviews recommend rasagiline as efficacious monotherapy for the control of symptoms of Parkinson’s disease or as a treatment to reduce ‘off’ time in patients with Parkinson’s disease with motor fluctuations and dyskinesia. In addition, clinical evidence supports the efficacy of MAO-B inhibitors in improving motor symptoms and daily living activities, and in delaying the need for levodopa therapy, according to guidelines from the National Institute for Health and Clinical Excellence.
No trials have been conducted to compare the therapeutic efficacy of rasagiline with other agents indicated for use as monotherapy in patients with early Parkinson’s disease. However, the favourable tolerability profile of rasagiline when given as monotherapy may offer an advantage over both selegiline and dopamine agonists. Rasagiline was well tolerated for up to 6.5 years during the TEMPO extension trial.[58,61–63] Notably, rasagiline did not increase the incidence of somnolence, hallucinations or confusion (adverse effects that occur frequently with selegiline and dopamine agonists) when administered at the approved 1 mg/day dose (section 5). Unlike selegiline, rasagiline is not metabolised to amphetamine or amphetamine derivatives (section 3.2), and is therefore devoid of sympathomimetic activity.[38,55]
Neuroprotective effects of rasagiline have been observed in vitro and in animal studies (section 2.2). Further investigation in the clinical setting is needed to determine whether this activity is borne out in patients with Parkinson’s disease. Long-term data from the TEMPO and TEMPO extension studies demonstrating that early-start rasagiline patients achieved a better degree of symptom control than delayed-start rasagiline patients suggest that rasagiline may confer a disease-modifying effect (section 4.1). After 2 years, almost half of the patients still in the study were adequately controlled by rasagiline monotherapy and did not require additional dopaminergic therapy (section 4.1). Of note, a large, randomised, double-blind study, the ADAGIO (Attenuation of Disease Progression with Rasagiline Once-Daily) study is currently underway with the aim of determining whether rasagiline has potential disease modifying effects in patients with very early Parkinson’s disease.
Rasagiline is also indicated for use as an adjunct to levodopa and has demonstrated efficacy in this indication in patients with moderate to advanced Parkinson’s disease in the PRESTO and LARGO trials (section 4.2). Results from the LARGO trial show that rasagiline and entacapone were significantly favoured over placebo in terms of daily ‘off’ time, daily ‘on’ time without dyskinesia, UPDRS ADL score during ‘off’ time and UPDRS motor score during ‘on’ time. Furthermore, the UPDRS motor score during ‘off’ time was significantly lower with rasagiline than with placebo in a LARGO substudy, whereas the effect of entacapone was not significant versus placebo in this substudy.[71,76] In a comparison of results from well designed clinical trials in patients with advanced Parkinson’s disease and motor fluctuations, the reduction in mean daily ‘off’ with rasagiline (1.9 hours) was similar to that observed with pramipexole, ropinirole and entacapone (1.2–1.9 hours) although cross-trial comparisons should be made with caution. Importantly, rasagiline improves the incidence of freezing of gait (section 4.2), a symptom which develops in most patients as the disease progresses and is not relieved by treatment with levodopa, dopamine agonists or COMT inhibitors.[9,103]
Rasagiline was generally well tolerated as adjunctive therapy when administered at the approved dose in patients with moderate to advanced disease. Although some dopaminergic effects, including dyskinesias, balance difficulty, weight loss, vomiting and anorexia, occurred more frequently with rasagiline 0.5–1 mg/day than with placebo in the PRESTO trial, there was no difference in the incidence of these adverse events between rasagiline 1 mg/day and placebo treatment groups in the LARGO trial (section 5). Importantly, when administered at the approved dosage, rasagiline does not potentiate cognitive and behavioural dopaminergic adverse effects such as hallucinations, confusion, depression and somnolence[74,106] and thus may be preferable to other treatments in older patients, who are more likely to suffer from cognitive impairment that can be exacerbated by dopamine agonists and COMT inhibitors. Between 40% and 60% of patients with advanced Parkinson’s disease may experience neuropsychiatric symptoms[2,9,107] and it is recommended that dopamine agonists and/or selegiline are discontinued or the dosages decreased in patients experiencing these symptoms. Although a small increased incidence of melanoma was observed with rasagiline in clinical trials (section 5), this type of cancer is associated with Parkinson’s disease[11,93,96] and may be related to levodopa treatment.[94,95]
In conclusion, rasagiline, administered once daily with no titration, is effective as initial monotherapy in patients with early Parkinson’s disease and as adjunctive therapy in patients with moderate to advanced disease and motor fluctuations. Rasagiline has a favourable efficacy and tolerability profile when administered at the approved dose. Thus, rasagiline, administered as a simple and convenient once-daily dosage regimen, is a well tolerated and effective option for monotherapy in patients with early Parkinson’s disease and as adjunctive therapy in patients with moderate to advanced disease.
During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article; changes based on any comments received were made on the basis of scientific and editorial merit.
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