Rasagiline (DB01367): A Comprehensive Pharmacological and Clinical Monograph

1.0 Introduction: Profile of a Second-Generation MAO-B Inhibitor

1.1 Overview and Therapeutic Context

Rasagiline is a second-generation, selective, and irreversible inhibitor of the enzyme monoamine oxidase type B (MAO-B), which holds a prominent position in the contemporary pharmacotherapeutic armamentarium for Parkinson's disease (PD).[1] It is indicated for the symptomatic management of idiopathic PD, serving a dual role as an initial monotherapy in the early stages of the disease and as an adjunctive therapy to levodopa in patients with more advanced disease experiencing motor fluctuations.[3]

Developed as a successor to the first-generation MAO-B inhibitor, selegiline, Rasagiline was engineered to retain the therapeutic benefits of MAO-B inhibition while improving upon the pharmacological profile of its predecessor. Key differentiating features that have defined its clinical utility include a convenient once-daily dosing regimen and, most notably, a metabolic pathway that does not produce amphetamine derivatives, thereby avoiding the associated sympathomimetic side effects.[1] As a small molecule therapeutic agent, Rasagiline represents a significant milestone in the targeted management of dopaminergic dysfunction in PD.[3]

1.2 Rationale for Development

The development of Rasagiline was driven by a clear and unmet clinical need in the management of Parkinson's disease. The cornerstone of PD therapy, levodopa, while highly effective, is associated with the emergence of long-term motor complications, including the "wearing-off" phenomenon and dyskinesias, in a majority of patients.[7] This created a demand for therapeutic strategies that could either delay the need for levodopa initiation or manage its complications once they arise.

The first-generation MAO-B inhibitor, selegiline, demonstrated the clinical value of this mechanism but possessed certain limitations, primarily related to its metabolism into L-methamphetamine and L-amphetamine, which were linked to undesirable side effects such as insomnia and cardiovascular stimulation.[1] The central rationale for Rasagiline's development was, therefore, to create a MAO-B inhibitor with a "cleaner" pharmacological profile, devoid of amphetamine metabolites, and with optimized pharmacokinetics allowing for once-daily administration.[1] Beyond symptomatic control, a compelling body of preclinical evidence suggested that Rasagiline possessed intrinsic neuroprotective properties, a finding that fueled a rigorous and extensive clinical development program aimed at exploring its potential to slow the progression of the underlying disease—a tantalizing but ultimately elusive goal that has become a defining part of its scientific narrative.[1]

2.0 Chemical Profile and Pharmaceutical Formulation

2.1 Chemical Identity and Stereochemistry

Rasagiline is a small molecule belonging to the propargylamine class of compounds, characterized by an indane chemical scaffold.[3] Its precise chemical identity is fundamental to its pharmacological activity.

• Systematic (IUPAC) Name: (1R)-N-propargylindan-1-amine, also designated as 1-Indanamine, N-2-propynyl-, (R)-.[3]
• Chemical Formula and Molecular Weight: The chemical formula for the rasagiline base is C12​H13​N. Its average molecular weight is 171.2383 g/mol, with a monoisotopic mass of 171.104799421 g/mol.[3]
• CAS Number: The unique identifier for rasagiline is CAS number 136236-51-6.[3]
• Chemical Structure: The molecule is an indane derivative, defined by a benzene ring fused to a cyclopentane ring. An amino group at the 1-position of the indane ring is substituted with a propargyl group (prop-2-yn-1-yl).[1] This propargylamine moiety is the critical pharmacophore responsible for the drug's mechanism of action. It enables the formation of an irreversible, covalent bond with the flavin adenine dinucleotide (FAD) cofactor of the MAO-B enzyme, leading to its inactivation.[1]

A crucial aspect of Rasagiline's chemical nature is its stereospecificity. The molecule exists as a chiral compound, and Rasagiline is specifically the R-(+)-enantiomer of a racemic mixture known as AGN-1135.[13] The decision to develop the single R-enantiomer was based on profound pharmacological differences between the two isomers. The R-(+)-enantiomer (Rasagiline) possesses virtually all the MAO-B inhibitory activity, demonstrating a potency that is approximately 1,000-fold greater than its S-(-)-enantiomer counterpart (TVP-1022). Furthermore, the S-enantiomer exhibits poor selectivity for MAO-B over MAO-A.[13] Isolating the R-enantiomer was a deliberate and rational drug design strategy to maximize the desired therapeutic effect (potent and selective MAO-B inhibition) while minimizing potential off-target activity (MAO-A inhibition), which could lead to undesirable side effects. This focus on a purified, stereospecific active isomer is a hallmark of second-generation drug development and is central to Rasagiline's optimized pharmacological profile.

2.2 Pharmaceutical Formulation and Presentation

For clinical use, Rasagiline is formulated and marketed as its mesylate (methanesulfonate) salt, a decision that enhances the compound's stability and solubility properties.[14]

• Salt Form: Rasagiline mesylate has the empirical formula (C12​H13​N)CH4​SO3​ and a corresponding molecular weight of 267.34 g/mol.[15]
• Physical Properties: The mesylate salt presents as a white to off-white crystalline powder that is freely soluble in water and ethanol, facilitating its formulation into an oral dosage form.[15]
• Dosage Forms and Strengths: Rasagiline is available for oral administration as tablets. These are formulated to contain rasagiline mesylate in amounts equivalent to 0.5 mg or 1 mg of the active rasagiline base.[5] The tablets are typically white to off-white, round, and debossed with markings to distinguish the different strengths.[5]
• Excipients: The tablet formulation contains several inactive ingredients necessary for its manufacture and stability, including mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid, and talc.[15]
• Storage and Handling: Regulatory guidelines specify that Rasagiline tablets should be dispensed in tight, light-resistant containers and stored at controlled room temperature, defined as 20°C to 25°C (68°F to 77°F).[5]

Table 1: Key Chemical and Physical Properties of Rasagiline
Identifier	Value
DrugBank ID	DB01367 3
CAS Number	136236-51-6 3
Chemical Formula (Base)	C12​H13​N 3
Molecular Weight (Base)	171.24 g/mol 12
Chemical Formula (Mesylate Salt)	C12​H13​N⋅CH4​O3​S 15
Molecular Weight (Mesylate Salt)	267.34 g/mol 15
IUPAC Name	(1R)-N-propargylindan-1-amine 3
Synonyms	Azilect, (R)-N-2-Propynyl-1-indanamine, AGN-1135 3
Appearance	White to off-white powder 15
Solubility	Freely soluble in water and ethanol 15
Chirality	R-(+)-enantiomer 13

3.0 Pharmacodynamics: Mechanism of Action and Cellular Effects

3.1 Primary Mechanism: Selective and Irreversible MAO-B Inhibition

The principal pharmacodynamic action of Rasagiline is its function as a potent, selective, and irreversible inhibitor of monoamine oxidase type B (MAO-B).[1] MAO-B is a mitochondrial flavoenzyme that plays a critical role in the catabolism of catecholamines. Within the human brain, MAO-B is the predominant isoform and is primarily responsible for the metabolic degradation of dopamine.[3] The pathophysiology of Parkinson's disease is defined by a profound loss of dopaminergic neurons in the substantia nigra, leading to a state of dopamine deficiency in the striatum.

Rasagiline's therapeutic effect is a direct consequence of its ability to counteract this process. By irreversibly inhibiting MAO-B, Rasagiline reduces the breakdown of dopamine within the striatum. This action leads to an increase in the extracellular concentration of dopamine and a subsequent enhancement of dopaminergic neurotransmission, which helps to compensate for the diminished endogenous dopamine synthesis.[3] This restoration of dopaminergic tone is the mechanism believed to mediate the beneficial effects of Rasagiline on the motor symptoms of PD.[3]

The inhibition is achieved through a "suicide inhibition" mechanism, wherein the propargylamine moiety of Rasagiline forms a stable, covalent adduct with the N5 atom of the enzyme's FAD cofactor, rendering the enzyme molecule permanently non-functional.[1] This irreversible binding has profound clinical implications. The duration of the drug's effect is not dictated by its presence in the plasma but rather by the rate at which the body can synthesize new MAO-B enzyme molecules. This biological turnover rate is slow, on the order of days to weeks. Consequently, platelet MAO-B activity, a peripheral marker of central enzyme inhibition, remains suppressed for at least one week following the last dose of Rasagiline.[15] This long-lasting pharmacodynamic footprint, despite a short pharmacokinetic half-life, is the fundamental basis for the convenient and adherence-promoting once-daily dosing regimen of Rasagiline.[1]

3.2 Selectivity Profile (MAO-B vs. MAO-A)

A defining feature of Rasagiline is its high degree of selectivity for the MAO-B isoenzyme over the MAO-A isoenzyme. In vitro assays demonstrate that Rasagiline is 30 to 100 times more potent as an inhibitor of MAO-B compared to MAO-A.[13] This selectivity is quantified by its half-maximal inhibitory concentration (

IC50​) values in rat brain tissue, which are approximately 4.43 nM for MAO-B versus 412 nM for MAO-A.[12]

This selectivity is of paramount clinical importance. The MAO-A isoform is predominantly located in the gastrointestinal tract and liver, where it is responsible for the metabolism of dietary biogenic amines, most notably tyramine.[3] When MAO-A is inhibited, ingestion of tyramine-rich foods (e.g., aged cheeses, cured meats, certain wines) can lead to a massive release of norepinephrine, resulting in a potentially fatal hypertensive crisis known as the "cheese effect".[4]

At its recommended therapeutic dose of 1 mg once daily, Rasagiline's selectivity for MAO-B is sufficiently high that it does not cause clinically significant inhibition of intestinal MAO-A. Controlled tyramine challenge studies in humans have confirmed that Rasagiline at this dose does not meaningfully potentiate the pressor effects of tyramine.[6] This favorable safety profile allows Rasagiline to be prescribed without the strict dietary tyramine restrictions that are mandatory for older, non-selective MAO inhibitors.[5] It is crucial to recognize, however, that this selectivity is a dose-dependent phenomenon. At supratherapeutic doses, Rasagiline's selectivity for MAO-B diminishes, and it would eventually inhibit MAO-A as well.[13] This reality is reflected in a cautious regulatory stance; despite the positive results of challenge studies, official prescribing information advises patients to avoid foods with extremely high tyramine content, acknowledging a low but non-zero risk, particularly in the context of potential overdose or drug interactions that could elevate Rasagiline concentrations into a non-selective range.[14]

3.3 Ancillary and Neuroprotective Mechanisms

In addition to its primary mechanism of MAO-B inhibition, an extensive body of preclinical research has revealed that Rasagiline and its primary metabolite possess neuroprotective and anti-apoptotic properties that are independent of MAO inhibition.[1] These findings have generated considerable scientific interest and formed the basis for clinical trials investigating a potential disease-modifying role for the drug.

One of the proposed neuroprotective mechanisms involves the modulation of cell survival pathways. Rasagiline has been shown to act as an activator of the anti-apoptotic protein Bcl-2, a key regulator of the mitochondrial cell death pathway.[3] Concurrently, it has been demonstrated to reduce the activation of caspase-3, a critical executioner enzyme in the apoptotic cascade.[20] In various cellular and animal models, Rasagiline has shown a protective effect against neuronal death induced by a range of insults, including neurotoxins like 6-hydroxydopamine and MPTP, as well as ischemic injury.[12]

Significantly, the major metabolite of Rasagiline, (R)-1-aminoindan, also contributes to this pharmacological narrative. While this metabolite is devoid of MAO-B inhibitory activity, it has independently demonstrated neuroprotective effects in preclinical models.[5] This discovery was a key point of differentiation from selegiline, whose amphetamine metabolites are pharmacologically active but in a potentially undesirable, sympathomimetic manner. The fact that Rasagiline's metabolite might contribute a beneficial, non-dopaminergic effect created a compelling scientific story and provided a strong additional rationale for pursuing the large-scale ADAGIO clinical trial, which was designed to determine if these promising preclinical neuroprotective signals could translate into a tangible, disease-modifying benefit in patients with Parkinson's disease.[2]

4.0 Pharmacokinetics: A Profile of Disposition (ADME)

4.1 Absorption

Following oral administration, Rasagiline is absorbed rapidly from the gastrointestinal tract. Peak plasma concentrations (Cmax) are typically reached within a short timeframe of approximately 0.5 to 1 hour.[5] The drug undergoes substantial first-pass metabolism in the liver, which limits its systemic availability. The absolute bioavailability of an oral dose of Rasagiline is estimated to be around 36%.[15]

The presence of food in the stomach can influence the absorption profile. Co-administration with a high-fat meal does not significantly alter the time to reach peak concentration (Tmax), but it does lead to a notable decrease in Cmax by approximately 60% and a more modest decrease in the total drug exposure, or area under the curve (AUC), by about 20%. Because the reduction in overall exposure (AUC) is not considered to be clinically substantial, Rasagiline can be administered to patients with or without food, providing flexibility in its dosing schedule.[5]

4.2 Distribution

Rasagiline exhibits extensive distribution into body tissues, a characteristic reflected by its large volume of distribution (Vd). Reported values for Vd vary, with some sources citing an apparent volume of distribution (Vd/F) of 87 L after oral dosing and others reporting a mean Vd of 243 L following a single intravenous dose.[3] This large volume indicates that the drug does not remain confined to the bloodstream but distributes widely throughout the body, consistent with its ability to cross the blood-brain barrier and exert its effects within the central nervous system.[20]

The extent of Rasagiline's binding to plasma proteins is reported with some variability across sources, with figures ranging from approximately 60-70% to as high as 88-94%.[3] More specifically, the mean binding to human albumin, the primary binding protein, has been reported as 61-63%.[3] This moderate-to-high degree of protein binding is not anticipated to be a significant source of clinically relevant drug interactions resulting from displacement of or by other highly protein-bound drugs.

4.3 Metabolism

Rasagiline undergoes extensive and nearly complete biotransformation, primarily in the liver, before it is excreted from the body.[3] This hepatic metabolism is the main route of clearance for the drug.

The metabolic process is heavily dependent on the cytochrome P450 (CYP) enzyme system. In vitro studies have definitively identified CYP1A2 as the major isoenzyme responsible for the metabolism of Rasagiline.[3] This reliance on a single primary metabolic pathway makes Rasagiline susceptible to significant pharmacokinetic interactions with drugs that either inhibit or induce CYP1A2 activity. For instance, co-administration with a potent CYP1A2 inhibitor like the antibiotic ciprofloxacin has been shown to increase the AUC of Rasagiline by 83%, effectively doubling the patient's exposure to the drug.[5] This interaction is clinically significant and necessitates a dose reduction of Rasagiline to 0.5 mg daily in patients taking such inhibitors to prevent potential toxicity.[14] Conversely, potent inducers of CYP1A2, such as chemicals found in cigarette smoke, have the potential to increase the clearance of Rasagiline, thereby decreasing its plasma levels and potentially reducing its therapeutic efficacy.[5]

The main metabolic pathways for Rasagiline are N-dealkylation and/or hydroxylation. These processes yield several metabolites, the most significant of which is 1-Aminoindan.[5] As noted previously, this major metabolite is not an inhibitor of MAO-B. Following their formation, the parent drug and its metabolites undergo phase II metabolism, specifically conjugation with glucuronic acid, which facilitates their excretion.[3] An important feature of Rasagiline's metabolic profile is that it does not act as a significant inhibitor or inducer of other major CYP450 enzymes, which minimizes its potential to alter the metabolism of co-administered medications.[5]

4.4 Excretion

The elimination of Rasagiline and its metabolites occurs predominantly through the kidneys. Following administration of a radiolabeled oral dose, approximately 62-63% of the radioactivity is recovered in the urine over a period of several days. A smaller fraction, ranging from 7% to 22%, is eliminated via the feces.[3] The fact that less than 1% of the administered dose is excreted in the urine as unchanged parent drug serves as further confirmation of the extensive hepatic metabolism that Rasagiline undergoes.[3]

4.5 Pharmacokinetics in Special Populations

The pharmacokinetic profile of Rasagiline is generally consistent across different demographic groups, but it is significantly altered in the presence of hepatic impairment.

• Pharmacokinetic Half-Life: Rasagiline has a short terminal or steady-state elimination half-life, typically reported in the range of 0.6 to 3 hours.[3] As emphasized previously, this pharmacokinetic parameter is disconnected from the duration of the drug's pharmacological effect due to the irreversible nature of its binding to the MAO-B enzyme.[3]
• Linearity: The pharmacokinetics of Rasagiline are linear, meaning that exposure (AUC) increases proportionally with the dose over the clinically relevant range of 0.5 mg to 2 mg.[5]
• Hepatic Impairment: Liver dysfunction has a profound impact on Rasagiline clearance. In patients with mild hepatic impairment (Child-Pugh score 5-6), the AUC and Cmax are increased by approximately 80% and 38%, respectively. The effect is dramatically amplified in patients with moderate hepatic impairment (Child-Pugh score 7-9), where AUC and Cmax are increased by an average of 568% and 83%, respectively.[5] This massive increase in drug exposure in patients with moderate liver disease underscores the contraindication for its use in this population and the need for caution and dose adjustment in those with mild impairment.[4]
• Renal Impairment: In contrast to hepatic impairment, renal dysfunction does not significantly affect the pharmacokinetics of Rasagiline. Studies in patients with mild to moderate renal impairment have shown pharmacokinetic parameters similar to those in healthy subjects.[5]
• Elderly: Age does not appear to have a clinically significant influence on the pharmacokinetics of Rasagiline, and no age-based dose adjustments are required.[5]
• Genetic Polymorphisms: While metabolism is primarily via CYP1A2, pharmacogenetic studies have not found a strong association between common CYP1A2 alleles and pharmacokinetic variability. Emerging research suggests that genetic polymorphisms in the gene encoding the drug transporter P-glycoprotein (ABCB1), may play a more significant role in conditioning individual differences in Rasagiline exposure.[20]

Table 2: Summary of Pharmacokinetic Parameters of Rasagiline
Parameter	Value
Bioavailability (F)	~36% 15
Time to Peak (Tmax)	~0.5–1 hour 5
Volume of Distribution (Vd)	87–243 L 3
Plasma Protein Binding	~60–94% (variable reports) 3
Terminal Half-life (t½)	0.6–3 hours 3
Metabolism	Hepatic, primarily via CYP1A2 3
Excretion	Primarily renal (>60% as metabolites) 5
Effect of Food	Cmax​ ↓ ~60%, AUC ↓ ~20% (not clinically significant) 5

5.0 Clinical Efficacy in Parkinson's Disease: Analysis of Pivotal and Supportive Trials

The clinical utility of Rasagiline in the treatment of Parkinson's disease is supported by a robust program of randomized, controlled trials. These studies have firmly established its efficacy both as a monotherapy for patients in the early stages of the disease and as an adjunctive therapy for patients with more advanced disease who are experiencing motor fluctuations on levodopa. The four pivotal trials—TEMPO, PRESTO, LARGO, and ADAGIO—form the cornerstone of this evidence base.

Table 3: Summary of Pivotal Clinical Trials for Rasagiline
Trial Acronym (Name)	Population	Design	N (Patients)	Primary Endpoint	Key Result
TEMPO	Early PD (untreated)	Placebo-controlled, Delayed-start	~404 24	Change in total UPDRS score 25	Significant improvement in UPDRS vs. placebo for both 1mg and 2mg doses.5
PRESTO	Advanced PD (on Levodopa, with fluctuations)	Placebo-controlled	~472 24	Change in daily "OFF" time 24	Significant reduction in "OFF" time vs. placebo for both 0.5mg and 1mg doses.2
LARGO	Advanced PD (on Levodopa, with fluctuations)	Placebo- & Active-controlled (Entacapone)	~687 24	Change in daily "OFF" time 24	Significant reduction in "OFF" time vs. placebo; effect was similar to that of entacapone.24
ADAGIO	Early PD (untreated)	Placebo-controlled, Delayed-start	~1176 21	Slope of UPDRS change & final UPDRS difference 27	Met all primary endpoints for 1mg dose, but failed to meet endpoints for 2mg dose, leading to ambiguous results.6

5.1 Monotherapy in Early-Stage Disease: The TEMPO Trial

The efficacy of Rasagiline as an initial monotherapy was established in the TEMPO (TVP-1012 in Early Monotherapy for PD Outpatients) study.[2] This was a 26-week, multicenter, randomized, double-blind, placebo-controlled trial involving 404 patients with early-stage, untreated Parkinson's disease. Patients were randomized to receive Rasagiline 1 mg/day, Rasagiline 2 mg/day, or placebo.[5]

The primary measure of efficacy was the change from baseline to week 26 in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS), a standard tool for assessing the severity of PD symptoms.[25] The results demonstrated a clear and statistically significant symptomatic benefit for Rasagiline. Compared to the placebo group, patients treated with Rasagiline 1 mg/day experienced a mean improvement of 4.2 points on the total UPDRS score (p<0.0001), while those on the 2 mg/day dose showed a mean improvement of 3.56 points (p<0.0001).[5] Significant benefits were also observed on the motor and activities of daily living (ADL) subscales of the UPDRS.[24] Furthermore, the study noted a statistically significant and beneficial effect on the quality of life, as assessed by the PD-QUALIF scale.[5] The TEMPO trial thus provided definitive evidence for the efficacy of Rasagiline as a standalone treatment for managing the symptoms of early PD, offering clinicians a valuable option to initiate therapy and potentially delay the need for levodopa.[2]

5.2 Adjunctive Therapy in Fluctuating Disease: The PRESTO and LARGO Trials

For patients with more advanced PD who experience motor fluctuations as a complication of long-term levodopa therapy, two pivotal trials, PRESTO and LARGO, established the efficacy of Rasagiline as an adjunctive treatment.

The PRESTO (Parkinson's Rasagiline: Efficacy and Safety in the Treatment of Off) trial was a 26-week, randomized, double-blind, placebo-controlled study that enrolled 472 patients on stable levodopa therapy who were experiencing motor fluctuations.[24] The primary endpoint was the change from baseline in the total amount of daily "OFF" time, defined as periods of poor motor function.[24] The results were unequivocally positive. Both tested doses of Rasagiline, 0.5 mg/day and 1 mg/day, produced a statistically significant reduction in daily "OFF" time compared to placebo. The 1 mg dose decreased "OFF" time by approximately one hour more than placebo, corresponding to a 25% reduction from baseline and demonstrating its utility in managing the wearing-off phenomenon.[2]

The LARGO (Lasting effect in Adjunct therapy with RasaGiline) trial further solidified this role by comparing Rasagiline to another established adjunct therapy. This 18-week, randomized, double-blind study involved 687 levodopa-treated patients with motor fluctuations and had three treatment arms: Rasagiline 1 mg/day, the catechol-O-methyltransferase (COMT) inhibitor entacapone (200 mg with each levodopa dose), and placebo.[24] The primary endpoint was again the change in daily "OFF" time. Both active treatments were found to be superior to placebo. Rasagiline reduced mean daily "OFF" time by 0.78 hours, an effect that was statistically similar to the 0.80-hour reduction seen with entacapone.[5] By demonstrating non-inferiority to a standard-of-care adjunct therapy, the LARGO trial established Rasagiline as a robust and competitive option for managing motor fluctuations, offering an alternative mechanism of action (dopamine preservation) to achieve a similar clinical goal (reducing "OFF" time) as COMT inhibitors (levodopa extension).[24]

5.3 The Question of Neuroprotection: A Critical Analysis of the ADAGIO Trial

Perhaps the most discussed and controversial aspect of Rasagiline's clinical development is the investigation into its potential disease-modifying effects. This was formally tested in the ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) study, a large (N=1176), long-term (72-week), multicenter trial with a delayed-start design.[2] The study was born from the strong preclinical evidence of Rasagiline's neuroprotective properties.

The delayed-start design was employed in an attempt to separate a drug's purely symptomatic effects from a true disease-modifying effect. Patients with early, untreated PD were randomized into four groups: early-start Rasagiline 1 mg/day (for 72 weeks), delayed-start Rasagiline 1 mg/day (placebo for 36 weeks, then drug for 36 weeks), early-start Rasagiline 2 mg/day, and delayed-start Rasagiline 2 mg/day. The central hypothesis was that if Rasagiline slowed the underlying progression of the disease, the early-start groups would demonstrate a sustained benefit at the end of the 72-week study compared to the delayed-start groups, even after the latter had been receiving the symptomatic benefit of the drug for 36 weeks.

The results of the ADAGIO trial were highly ambiguous and generated significant debate. For the 1 mg dose, the study successfully met all three of its hierarchical primary endpoints, suggesting a potential disease-modifying effect.[6] However, for the 2 mg dose—a dose also proven to be symptomatically effective—the trial failed to meet its primary endpoints.[21] This biologically implausible divergence, where a lower dose appeared to work but a higher dose did not, fundamentally undermined the credibility of the positive findings for the 1 mg dose.

This conflicting outcome has rendered the ADAGIO trial a cautionary tale in clinical trial design for neurodegenerative diseases. Critics have highlighted several intrinsic flaws and potential confounding factors that likely contributed to the ambiguous result. These include the reliance on a subjective clinical rating scale (the UPDRS) to detect what was a very small statistical signal of slowed progression (a difference of only ~1.7 UPDRS points); the potential for functional unblinding of investigators and patients; and the possibility that the long-lasting symptomatic effects of the drug, particularly at the 2 mg dose, could not be adequately washed out or accounted for by the study design.[21] Ultimately, due to these inconclusive results, regulatory agencies such as the FDA and EMA have not granted Rasagiline a disease-modification indication. The scientific community remains divided, and the trial's legacy is that it failed to provide the definitive evidence needed to support the neuroprotection hypothesis in humans.[2]

5.4 Efficacy in Non-Motor Symptoms and Other Populations

While the primary focus of the pivotal trials was on motor symptoms, evidence has also emerged regarding Rasagiline's effects on non-motor aspects of PD and its efficacy in diverse populations.

• Depression: Depression is a common and debilitating non-motor symptom in PD. A meta-analysis has shown that Rasagiline has a large and clinically meaningful effect size relative to placebo for the improvement of depressive symptoms in patients with PD.[13] While caution is warranted when co-prescribing with antidepressants, pivotal trials did permit the use of certain antidepressants at limited doses without reporting adverse interactions, and case reports have described the successful use of Rasagiline even in combination with multiple antidepressants.[6]
• Apathy and Cognition: The potential benefit of Rasagiline for other non-motor symptoms is less clear. A Phase 4 clinical trial was initiated to specifically evaluate its efficacy in treating apathy in drug-naïve PD patients.[30] In the domain of cognition, one six-month study found that while Rasagiline provided the expected improvement in motor symptoms, it did not lead to significant changes on a battery of neuropsychological tests compared to placebo.[31]
• Global Populations: The efficacy and safety of Rasagiline have been confirmed in clinical trials conducted specifically in East Asian populations. Successful Phase 3 trials in Chinese and Korean patients with motor fluctuations have supported its approval and use in these regions, demonstrating its consistent therapeutic benefit across different ethnic groups.[32]

6.0 Safety, Tolerability, and Risk Management

6.1 Profile of Adverse Drug Reactions (ADRs)

The safety and tolerability profile of Rasagiline is well-characterized and is highly dependent on the clinical context in which it is used—namely, as a monotherapy in early disease versus as an adjunct to levodopa in more advanced disease. The adverse effects observed are largely predictable based on the drug's dopaminergic mechanism of action.

When used as a monotherapy in patients with early PD, Rasagiline is generally well-tolerated, with a side effect profile that is often comparable to placebo. In placebo-controlled trials, the most frequently reported adverse drug reactions (with an incidence of at least 3% and greater than placebo) included flu syndrome, arthralgia (joint pain), depression, and dyspepsia (indigestion).[14] Other common effects included headache and vertigo.[5]

When Rasagiline is used as an adjunctive therapy added to a stable regimen of levodopa, its safety profile reflects the potentiation of central dopaminergic stimulation. Consequently, the most common adverse reactions are those associated with excessive dopaminergic activity. These include dyskinesia (involuntary movements), which is the most prominent side effect in this setting, as well as accidental injury or falls, weight loss, postural hypotension, nausea and vomiting, dry mouth, constipation, and abnormal dreams.[14] Many of these dopaminergic side effects, particularly dyskinesia, can often be managed by reducing the dose of the concomitant levodopa, highlighting the direct cause-and-effect relationship.[14] Several of these effects, such as weight loss, postural hypotension, and dry mouth, have been shown to be dose-related.[14]

Table 4: Common Adverse Drug Reactions (≥3% and >Placebo) by Therapeutic Setting
Adverse Reaction	Monotherapy Setting (Incidence)	Adjunct to Levodopa Setting (Incidence)
Dyskinesia	Not significantly different from placebo	High incidence, often leading to levodopa dose reduction 14
Postural Hypotension	Low incidence	Common, dose-related 14
Nausea/Vomiting	Low incidence	Common 14
Dry Mouth	Low incidence	Common 14
Insomnia	Low incidence	Common 14
Dizziness/Vertigo	Common (as Vertigo) 5	Common (as Dizziness) 14
Depression	Common 14	Not typically a primary dopaminergic ADR
Arthralgia	Common 14	Common 14
Fall	Common	Common (as Accidental Injury/Fall) 14

6.2 Contraindications and Significant Warnings

The safe use of Rasagiline requires strict adherence to its contraindications and careful management of risks highlighted in regulatory warnings. These precautions are primarily designed to prevent severe, life-threatening drug interactions and to manage the potent dopaminergic effects of the medication.

Absolute Contraindications:

• Other MAO Inhibitors: Concomitant use with any other MAO inhibitor, whether selective (like selegiline) or non-selective, is strictly contraindicated. This includes over-the-counter products containing St. John's Wort. This combination poses a high risk of non-selective MAO inhibition, which can lead to a hypertensive crisis.[5]
• Certain Analgesics and Other Drugs: Co-administration with the opioids meperidine, tramadol, methadone, and propoxyphene is contraindicated due to a high risk of precipitating serotonin syndrome.[4] Use with the cough suppressant dextromethorphan (risk of psychosis) and the muscle relaxant cyclobenzaprine is also contraindicated.[14]
• Washout Period: A mandatory washout period of at least 14 days must be observed between the discontinuation of Rasagiline and the initiation of any of the contraindicated medications listed above.[4]
• Hepatic Impairment: Rasagiline is contraindicated in patients with severe hepatic impairment due to the profound increase in drug exposure.[5]

Key Warnings and Precautions:

The FDA and EMA have mandated several important warnings on the prescribing information for Rasagiline, forming the basis of its risk management plan.

• Serotonin Syndrome: There is a risk of this potentially fatal syndrome when Rasagiline is combined with serotonergic antidepressants (e.g., SSRIs, SNRIs, tricyclic antidepressants). Concomitant use is not recommended, and if necessary, requires extreme caution and a sufficient washout period.[14]
• Hypertension: Rasagiline may cause or exacerbate hypertension. Blood pressure should be monitored, especially upon initiation of therapy.[14]
• Somnolence and Sudden Onset of Sleep: Patients may experience excessive daytime sleepiness or, in rare cases, may fall asleep suddenly during activities of daily living, including driving, sometimes without prior warning signs. Patients must be counseled on this risk and cautioned about operating heavy machinery.[5]
• Hypotension and Orthostatic Hypotension: The drug can cause or worsen orthostatic hypotension, particularly during the first two months of treatment and when used in combination with levodopa. Patients should be advised to rise slowly from sitting or lying positions.[14]
• Hallucinations and Psychotic-Like Behavior: Rasagiline can induce or worsen psychosis, including hallucinations, confusion, and aggressive behavior. It is generally not recommended for patients with a major psychotic disorder.[14]
• Impulse Control Disorders (ICDs): Like other dopaminergic therapies, Rasagiline can be associated with the emergence of intense, uncontrollable urges, such as pathological gambling, increased libido, compulsive spending, or binge eating. Clinicians must proactively monitor patients and caregivers for the development of these behaviors.[5]
• Melanoma: Epidemiological studies indicate that patients with PD have a higher baseline risk of developing melanoma. While a causal link to Rasagiline is not established, regular dermatological screening is recommended for all patients on the medication.[5]
• Withdrawal-Emergent Hyperpyrexia and Confusion: Abrupt cessation or rapid dose reduction of Rasagiline can lead to a symptom complex resembling neuroleptic malignant syndrome, characterized by high fever, confusion, and rigidity. Discontinuation should be done under medical supervision.[14]

6.3 Drug-Drug and Drug-Food Interactions

The potential for interactions is primarily driven by Rasagiline's metabolism via CYP1A2 and its MAO-B inhibitory activity.

Drug-Drug Interactions:

• CYP1A2 Inhibitors: As previously noted, potent inhibitors of the CYP1A2 enzyme, such as ciprofloxacin and fluvoxamine, can significantly increase plasma concentrations of Rasagiline. In patients taking such inhibitors, the daily dose of Rasagiline must be reduced to 0.5 mg to avoid excessive exposure and potential toxicity.[5]
• CYP1A2 Inducers: Conversely, substances that induce CYP1A2 activity, such as the polycyclic aromatic hydrocarbons in cigarette smoke, may increase the metabolism of Rasagiline, potentially leading to lower plasma levels and reduced efficacy. This should be considered in patients who smoke.[5]
• Serotonergic Agents: The interaction with antidepressants and certain opioids is the most critical and is managed through contraindication or recommendations against co-administration due to the risk of serotonin syndrome.[5]

Drug-Food Interactions (The Tyramine Issue):

The risk of a tyramine-induced hypertensive crisis is the classic interaction associated with MAO inhibitors. However, due to Rasagiline's high selectivity for MAO-B at its recommended therapeutic dose, this risk is substantially mitigated.

• Multiple controlled tyramine challenge studies have demonstrated that Rasagiline at a dose of 1 mg/day can be used safely without the need for dietary tyramine restrictions.[5]
• However, because the selectivity for MAO-B is dose-dependent and diminishes at higher concentrations, a theoretical risk remains. The FDA label reflects this with a cautious recommendation for patients to avoid foods containing very large amounts of tyramine (defined as more than 150 mg). This guidance is based on a risk-mitigation principle, acknowledging rare post-marketing reports of hypertensive reactions and the potential for increased risk in situations of overdose or in individuals with impaired metabolism.[4]

7.0 Comparative Analysis: Rasagiline in the Context of MAO-B Inhibitors

The therapeutic positioning of Rasagiline is best understood through comparison with the other primary MAO-B inhibitors used in Parkinson's disease: the first-generation agent, selegiline, and the newer, multi-action agent, safinamide.

Table 5: Comparative Profile of MAO-B Inhibitors: Rasagiline, Selegiline, and Safinamide
Feature	Rasagiline	Selegiline	Safinamide
Mechanism	MAO-B Inhibition	MAO-B Inhibition, TAAR1 Agonism	MAO-B Inhibition, Glutamate Modulation
Reversibility	Irreversible, Covalent 1	Irreversible, Covalent 36	Reversible, Competitive 36
Metabolism	Hepatic (CYP1A2) 5	Hepatic	Hepatic
Key Metabolites	1-Aminoindan (non-amphetamine) 13	L-methamphetamine, L-amphetamine 13	Inert metabolites 29
Dosing Frequency	Once-daily 4	Twice-daily (oral) / Once-daily (ODT) 37	Once-daily 38
Primary Use Case	Monotherapy or Adjunct 5	Adjunct (primarily) 37	Adjunct only 38
Tyramine Risk (Std. Dose)	Very Low 6	Low 38	Very Low 38
Unique Feature	"Clean" metabolic profile	Amphetamine metabolites	Dual mechanism of action

7.1 Rasagiline vs. Selegiline (First vs. Second Generation)

The comparison between Rasagiline and selegiline is a classic example of second-generation drug development aimed at improving upon a first-in-class agent.

• Potency and Efficacy: In vitro, Rasagiline is approximately 5 to 10 times more potent than selegiline as an inhibitor of MAO-B.[13] Despite this difference in potency, their clinical efficacy appears to be broadly similar. An indirect meta-analysis of placebo-controlled trials in early PD concluded that the two drugs had comparable efficacy in improving motor symptoms as measured by the UPDRS.[39] In contrast, another analysis suggested selegiline might be more effective as an adjunct to levodopa.[40] A real-world observational study from Israel, where selegiline was the standard of care before being largely replaced by Rasagiline, found that patients initiated on Rasagiline monotherapy tended to require the addition of levodopa or a dopamine agonist sooner than those started on selegiline, although this finding was complicated by baseline differences between the groups.[41]
• Metabolism and Side Effects: The most significant and clinically impactful difference lies in their metabolic pathways. Selegiline is metabolized in the body to L-methamphetamine and L-amphetamine.[13] These active metabolites possess sympathomimetic and psychostimulant properties and have long been associated with side effects such as insomnia, anxiety, and potential cardiovascular stimulation.[1] In stark contrast, Rasagiline's major metabolite is (R)-1-aminoindan, which is not an amphetamine derivative and lacks these stimulant effects.[1] This "cleaner" metabolic profile was a primary driver in the shift in clinical practice away from selegiline and towards Rasagiline, as it offered a way to achieve MAO-B inhibition without the pharmacological "baggage" of amphetamine byproducts.[9]
• Mechanism Nuances: Beyond metabolism, emerging research suggests more subtle differences in their mechanisms. Selegiline and its methamphetamine metabolite appear to have an additional "dopaminergic enhancer" effect, possibly through agonism at the trace amine-associated receptor 1 (TAAR1). Rasagiline does not share this property and may even act as a TAAR1 antagonist.[42] This difference in receptor pharmacology could contribute to some of the observed variations in their clinical effects and side effect profiles.

7.2 Rasagiline vs. Safinamide (Irreversible vs. Reversible/Dual-Action)

The introduction of safinamide represents a further evolution in the MAO-B inhibitor class, moving from agents with a singular mechanism to those with multiple, complementary actions.

• Mechanism: The fundamental difference is twofold. First, while Rasagiline is an irreversible inhibitor, safinamide is a selective and reversible inhibitor of MAO-B.[36] Second, and more importantly, safinamide possesses a distinct second mechanism of action: it modulates voltage-gated sodium and calcium channels, which results in the inhibition of excessive, stimulated glutamate release in the brain.[29] Given that glutamatergic overactivity is also implicated in the pathophysiology of PD, safinamide is considered a dual-action or multi-target drug.
• Indications: This difference in mechanism is reflected in their approved indications. Rasagiline is approved for use across the disease spectrum, as both a monotherapy in early PD and as an adjunct therapy in later stages.[5] Safinamide, however, is approved exclusively as an adjunctive therapy for levodopa-treated patients who are experiencing motor fluctuations.[29]
• Clinical Data and Switching: The dual mechanism of safinamide provides a clear rationale for its use in patients who are not optimally controlled on other therapies, including Rasagiline. Clinical studies have demonstrated that in patients with fluctuating PD, switching from Rasagiline to safinamide can lead to further improvements in "OFF" time and can also improve non-motor symptoms such as pain and sleep disturbances.[29] This suggests that the added benefit is derived from the novel glutamatergic mechanism, not simply from more potent MAO-B inhibition. This has carved out a specific therapeutic niche for safinamide as a second-line adjunct therapy when initial adjuncts prove insufficient.

8.0 Regulatory and Commercial Landscape

8.1 Global Regulatory Approvals

Rasagiline was developed through a collaboration between the Israeli pharmaceutical company Teva Pharmaceutical Industries and the Technion-Israel Institute of Technology.[1] Its path to becoming a global standard of care involved a well-executed, phased series of regulatory approvals in major markets worldwide.

• EMA Approval: The first major regulatory milestones were achieved in early 2005, with approvals in Israel and subsequently across the European Union by the European Medicines Agency (EMA).[2] The reference product in the EU is Azilect. Following patent expiry, the EMA began authorizing generic versions of Rasagiline around 2016, such as Rasagiline Viatris and Rasagiline ratiopharm, based on demonstrations of bioequivalence to Azilect.[17]
• FDA Approval: In the United States, Rasagiline was approved by the Food and Drug Administration (FDA) on May 16, 2006, under the brand name Azilect.[13] The initial indication was for both monotherapy and adjunct therapy to levodopa. In June 2014, the FDA expanded the label to explicitly note its use as an adjunct to dopamine agonists as well.[2]
• Other Regions: The drug's global reach was extended through approvals in numerous other countries, including Canada and Japan. In Japan, a key market with high unmet need, Teva entered into a strategic agreement with Takeda Pharmaceutical Company to commercialize the drug, which was approved there in 2018.[2] Rasagiline is now available in over 40 countries.[47]

This successful global development strategy—from academic-industrial collaboration to sequential approvals and strategic regional partnerships—allowed Teva to maximize the drug's commercial potential. By 2010, annual sales of Azilect had already surpassed $200 million, solidifying its status as a blockbuster therapy for Parkinson's disease.[48]

8.2 Brand Names and Manufacturers

• Primary Brand Name: The original and most widely recognized brand name for Rasagiline is Azilect, developed and marketed by Teva Pharmaceuticals.[1]
• Generic Market: The expiration of key patents, including a significant US patent in 2012, opened the door for generic competition.[48] This has led to the emergence of a robust market for generic rasagiline tablets. Numerous pharmaceutical companies now manufacture and market generic versions, making the treatment more accessible and affordable. These manufacturers include Teva itself (as a generic), Alkem Laboratories, Aurobindo Pharma, Chartwell Rx, Macleods Pharmaceuticals, Micro Labs, Mylan (now part of Viatris), and Torrent Pharmaceuticals, among many others.[48]
• Commercial Agreements: To facilitate its global reach, Teva established several key commercial partnerships. Notable agreements include a long-term arrangement with H. Lundbeck A/S for the joint development and marketing of Azilect in Europe and other markets, and the aforementioned agreement with Takeda for commercialization in Japan.[46]

9.0 Expert Synthesis and Concluding Remarks

9.1 Integrated Assessment of Therapeutic Value

Rasagiline has firmly established itself as a cornerstone therapy in the management of Parkinson's disease. Its value lies in its proven symptomatic efficacy across the disease spectrum, from the mild symptoms of early disease to the complex motor fluctuations of advanced disease. Its widespread adoption and sustained clinical use can be attributed to a constellation of favorable attributes. The convenient once-daily dosing regimen, a direct result of its irreversible mechanism of action, enhances patient adherence. Most critically, its "clean" metabolic profile, which avoids the generation of amphetamine byproducts characteristic of its predecessor selegiline, offers a superior tolerability profile with respect to stimulant-related side effects. This combination of reliable efficacy, convenient administration, and an improved safety profile relative to the first-generation agent represents a significant therapeutic advance and is the primary reason for its success.

9.2 Balancing Efficacy, Safety, and Unresolved Questions

The therapeutic benefits of Rasagiline are well-documented and not in dispute. However, its safe and effective use requires a nuanced understanding of its risks and limitations. When used as a monotherapy, it is generally a benign and well-tolerated agent. When used as an adjunct to levodopa, its safety profile becomes a reflection of potentiated dopaminergic stimulation, necessitating careful monitoring for and management of side effects like dyskinesia, orthostatic hypotension, and hallucinations. The most critical safety considerations revolve around the absolute contraindications with other MAO inhibitors and specific serotonergic agents, which demand meticulous medication reconciliation to prevent potentially fatal interactions like hypertensive crisis and serotonin syndrome.

The most prominent unresolved question surrounding Rasagiline remains that of neuroprotection. The ambitious ADAGIO trial, designed to provide a definitive answer, instead yielded ambiguous and controversial results that have failed to convince the scientific and regulatory communities. While the preclinical evidence for neuroprotection is compelling, the lack of conclusive clinical data means that Rasagiline must be prescribed for its proven symptomatic benefits alone. The ADAGIO trial's outcome serves as a powerful lesson on the profound challenges of demonstrating disease modification in slowly progressive neurodegenerative disorders using current clinical trial methodologies.

9.3 Recommendations for Clinical Practice and Future Research

For Clinical Practice: Rasagiline remains an excellent and highly recommended therapeutic option. It is a first-line choice for monotherapy in patients with early, mild Parkinson's disease, where it can effectively control symptoms and delay the need for levodopa. In patients with more advanced disease experiencing motor fluctuations, it is a valuable and competitive adjunctive therapy, proven to reduce "OFF" time. The choice of Rasagiline versus other agents, particularly the newer MAO-B inhibitor safinamide, should be individualized. This decision should be based on the patient's specific clinical profile, including the presence of non-motor symptoms like pain (where safinamide may offer an advantage), their list of co-medications (especially CYP1A2 inhibitors), and their overall tolerability.

For Future Research: The field would benefit significantly from well-designed, head-to-head clinical trials directly comparing the available MAO-B inhibitors (Rasagiline, selegiline, and safinamide) on a comprehensive range of both motor and non-motor outcomes. The legacy of the ADAGIO trial underscores an urgent and critical need for the development, validation, and regulatory acceptance of objective biomarkers of disease progression (e.g., advanced neuroimaging, fluid biomarkers). The availability of such tools is likely a prerequisite for any future trial to successfully prove a disease-modifying effect for any agent in Parkinson's disease. Finally, further mechanistic investigation into the non-MAO-B-inhibitory effects of Rasagiline, such as its interaction with the Bcl-2 family of proteins, is warranted to better understand its full spectrum of biological activity.

Works cited

1. Rasagiline | 136236-51-6 - ChemicalBook, accessed July 31, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2459598.htm
2. Rasagiline - Second-Generation MAO-B Inhibitor for the Treatment ..., accessed July 31, 2025, https://www.clinicaltrialsarena.com/projects/rasagiline-parkinsons-disease/
3. Rasagiline: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 31, 2025, https://go.drugbank.com/drugs/DB01367
4. Rasagiline (oral route) - Side effects & dosage - Mayo Clinic, accessed July 31, 2025, https://www.mayoclinic.org/drugs-supplements/rasagiline-oral-route/description/drg-20068415
5. Rasagiline 1 mg Tablets - Summary of Product Characteristics ..., accessed July 31, 2025, https://www.medicines.org.uk/emc/product/10016/smpc
6. Successful Use of Rasagiline in Combination with Two Antidepressants: A Case Report, accessed July 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3552466/
7. Study Details | Clinical Trial of Rasagiline in Levodopa-Treated Parkinson's Disease Patients With Motor Fluctuations | ClinicalTrials.gov, accessed July 31, 2025, https://www.clinicaltrials.gov/study/NCT01736891
8. Rasagiline for the management of Parkinson's disease - Open Access Journals, accessed July 31, 2025, https://www.openaccessjournals.com/articles/rasagiline-for-the-management-of-parkinsons-disease.pdf
9. Switch from selegiline to rasagiline is beneficial in patients with Parkinson's disease | Request PDF - ResearchGate, accessed July 31, 2025, https://www.researchgate.net/publication/233805736_Switch_from_selegiline_to_rasagiline_is_beneficial_in_patients_with_Parkinson's_disease
10. The role of rasagiline in the treatment of Parkinson's disease - PMC, accessed July 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2877525/
11. Rasagiline | C12H13N | CID 3052776 - PubChem, accessed July 31, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Rasagiline
12. Rasagiline | CAS# 136236-51-6 | Monoamine Oxidase Inhibitor - MedKoo Biosciences, accessed July 31, 2025, https://www.medkoo.com/products/32408
13. Rasagiline - Wikipedia, accessed July 31, 2025, https://en.wikipedia.org/wiki/Rasagiline
14. Rasagiline - accessdata.fda.gov, accessed July 31, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201971orig1s000lbl.pdf
15. AZILECT® (rasagiline) Tablets, 0.5 and 1 mg - CPY Document, accessed July 31, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021641s000_Azilect_PRNTLBL.pdf
16. RASAGILINE MESYLATE - Inxight Drugs, accessed July 31, 2025, https://drugs.ncats.io/substance/LH8C2JI290
17. Rasagiline Viatris (previously Rasagiline Mylan) | European Medicines Agency (EMA), accessed July 31, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/rasagiline-viatris
18. Rasagiline (CAS 136236-51-6) - Cayman Chemical, accessed July 31, 2025, https://www.caymanchem.com/product/14917/rasagiline
19. Rasagiline ((R)-AGN1135) | MAO Inhibitor - MedchemExpress.com, accessed July 31, 2025, https://www.medchemexpress.com/rasagiline.html
20. Polymorphism of Drug Transporters, Rather Than Metabolizing Enzymes, Conditions the Pharmacokinetics of Rasagiline - MDPI, accessed July 31, 2025, https://www.mdpi.com/1999-4923/14/10/2001
21. Rasagiline, Parkinson neuroprotection, and delayed-start trials: Still ..., accessed July 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2865777/
22. Rasagiline – a novel MAO B inhibitor in Parkinson's disease therapy - PMC, accessed July 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2386362/
23. Label: AZILECT- rasagiline mesylate tablet - DailyMed, accessed July 31, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eb558270-1b12-4704-9b09-39f668f30529
24. Clinical trials with rasagiline - Neurology.org, accessed July 31, 2025, https://www.neurology.org/doi/10.1212/WNL.66.10_suppl_4.S80
25. A controlled trial of rasagiline in early Parkinson disease: The tempo study - Mayo Clinic, accessed July 31, 2025, https://mayoclinic.elsevierpure.com/en/publications/a-controlled-trial-of-rasagiline-in-early-parkinson-disease-the-t
26. Rasagiline ratiopharm | European Medicines Agency (EMA), accessed July 31, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/rasagiline-ratiopharm
27. A Randomized Placebo Controlled Study to Show That Rasagiline May Slow Disease Progression for Parkinson's Disease (ADAGIO) - ClinicalTrials.gov, accessed July 31, 2025, https://clinicaltrials.gov/study/NCT00256204
28. Rasagiline adjunct therapy in patients with Parkinson's disease: post hoc analyses of the PRESTO and LARGO trials - PubMed, accessed July 31, 2025, https://pubmed.ncbi.nlm.nih.gov/23849501/
29. Switching from Rasagiline to Safinamide as an Add-On Therapy ..., accessed July 31, 2025, https://www.mdpi.com/2076-3425/13/2/276
30. Rasagiline Unknown Status Phase 4 Trials for Drug-naïve Patients With Parkinson's Disease / Apathy Treatment - DrugBank, accessed July 31, 2025, https://go.drugbank.com/drugs/DB01367/clinical_trials?conditions=DBCOND0018612%2CDBCOND0061281&phase=4&purpose=treatment&status=unknown_status
31. Study Details | The Effect of Rasagiline on Cognition in Parkinson's Disease, accessed July 31, 2025, https://clinicaltrials.gov/study/NCT01382342
32. Rasagiline Completed Phase 1 Trials for Parkinson's Disease (PD) Treatment - DrugBank, accessed July 31, 2025, https://go.drugbank.com/drugs/DB01367/clinical_trials?conditions=DBCOND0053495&phase=1&purpose=treatment&status=completed
33. Rasagiline Completed Phase 3 Trials for Parkinson's Disease (PD) Treatment - DrugBank, accessed July 31, 2025, https://go.drugbank.com/drugs/DB01367/clinical_trials?conditions=DBCOND0053495&phase=3&purpose=treatment&status=completed
34. Rasagiline (Azilect): Uses, Side Effects, Dosage & Reviews - GoodRx, accessed July 31, 2025, https://www.goodrx.com/rasagiline/what-is
35. Rasagiline: MedlinePlus Drug Information, accessed July 31, 2025, https://medlineplus.gov/druginfo/meds/a606017.html
36. Different Generations of Type-B Monoamine Oxidase Inhibitors in Parkinson's Disease: From Bench to Bedside - PubMed, accessed July 31, 2025, https://pubmed.ncbi.nlm.nih.gov/30160213/
37. Zelapar vs. Azilect for Parkinson's Disease - GoodRx, accessed July 31, 2025, https://www.goodrx.com/compare/eldepryl-vs-azilect
38. MAO-B Inhibitors: Rasagiline, Selegiline & Safinamide, accessed July 31, 2025, https://drkharkar.com/rasalect-safinamide/
39. Comparative efficacy of selegiline versus rasagiline in the treatment of early Parkinson's disease - ResearchGate, accessed July 31, 2025, https://www.researchgate.net/publication/263817480_Comparative_efficacy_of_selegiline_versus_rasagiline_in_the_treatment_of_early_Parkinson's_disease
40. A multiple treatment comparison meta‐analysis of monoamine oxidase type B inhibitors for Parkinson's disease - PubMed Central, accessed July 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6089809/
41. Comparison of Selegiline and Rasagiline Therapies in Parkinson Disease: A Real-life Study, accessed July 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5028154/
42. Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline - MDPI, accessed July 31, 2025, https://www.mdpi.com/1422-0067/24/17/13334
43. MAO-B inhibitors (rasagiline, selegiline, safinamide) | Parkinson's UK, accessed July 31, 2025, https://www.parkinsons.org.uk/information-and-support/mao-b-inhibitors-rasagiline-selegiline-safinamide
44. Azilect (rasagiline mesylate) FDA Approval History - Drugs.com, accessed July 31, 2025, https://www.drugs.com/history/azilect.html
45. Drug Approval Package: Azilect (Rasagiline Mesylate) NDA #021641 - accessdata.fda.gov, accessed July 31, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021641s000_azilecttoc.cfm
46. TEVA AND TAKEDA AGREE TO COMMERCIALIZE RASAGILINE FOR PARKINSON'S DISEASE TREATMENT IN JAPAN, accessed July 31, 2025, https://www.takeda.com/newsroom/newsreleases/2014/teva-and-takeda-agree-to-commercialize-rasagiline-for-parkinsons-disease-treatment-in-japan/
47. Teva Announces AZILECT® (Rasagiline Tablets) Data to Be Presented at the 16th Annual International Congress of Parkinson's Disease and Movement Disorders, accessed July 31, 2025, https://ir.tevapharm.com/news-and-events/press-releases/press-release-details/2012/Teva-Announces-AZILECT-Rasagiline-Tablets-Data-to-Be-Presented-at-the-16th-Annual-International-Congress-of-Parkinsons-Disease-and-Movement-Disorders/default.aspx
48. Generic RASAGILINE MESYLATE INN entry, pharmaceutical patent expiration information and freedom to operate - DrugPatentWatch, accessed July 31, 2025, https://www.drugpatentwatch.com/p/generic/rasagiline+mesylate
49. Generic Azilect Availability - Drugs.com, accessed July 31, 2025, https://www.drugs.com/availability/generic-azilect.html
50. Rasagiline - Medthority, accessed July 31, 2025, https://www.medthority.com/fda/r/rasagiline/
51. Label: RASAGILINE tablet - DailyMed, accessed July 31, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e8771c7e-5ecf-47dc-a0fd-4d12e85631a6