2.1 General Dosing Recommendations

When rasagiline tablets are prescribed as monotherapy or as adjunct therapy in patients not taking levodopa, patients may start rasagiline tablets at the recommended dose of 1 mg administered orally once daily.

In patients taking levodopa, with or without other PD drugs (e.g., dopamine agonist, amantadine, anticholinergics), the recommended initial dose of rasagiline tablets is 0.5 mg once daily. If the patient tolerates the daily 0.5 mg dose, but a sufficient clinical response is not achieved, the dose may be increased to 1 mg once daily. When rasagiline tablets are used in combination with levodopa, a reduction of the levodopa dose may be considered, based upon individual response.

The recommended doses of rasagiline tablets should not be exceeded because of risk of hypertension [see Warnings and Precautions (5.1)].

2.2 Patients Taking Ciprofloxacin or Other CYP1A2 Inhibitors

Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of rasagiline tablets 0.5 mg once daily [see Warnings and Precautions (5.4), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].

2.3 Patients with Hepatic Impairment

Patients with mild hepatic impairment should not exceed a dose of rasagiline tablets 0.5 mg once daily. Rasagiline tablets should not be used in patients with moderate or severe hepatic impairment [see Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

5.1 Hypertension

Exacerbation of hypertension may occur during treatment with rasagiline tablets. Medication adjustment may be necessary if elevation of blood pressure is sustained. Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting rasagiline tablets.

In Study 3, rasagiline tablets (1 mg/day) given in conjunction with levodopa, produced an increased incidence of significant blood pressure elevation (systolic > 180 or diastolic > 100 mm Hg) of 4% compared to 3% for placebo [see Adverse Reactions (6.1)].

When used as an adjunct to levodopa (Studies 3 and 4), the risk for developing post-treatment high blood pressure (e.g., systolic > 180 or diastolic >100 mm Hg) combined with a significant increase from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for rasagiline tablets (2%) compared to placebo (1%).

Dietary tyramine restriction is not required during treatment with recommended doses of rasagiline tablets. However, certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine that could potentially cause severe hypertension because of tyramine interaction (including various clinical syndromes referred to as hypertensive urgency, crisis, or emergency) in patients taking rasagiline tablets, even at the recommended doses, due to increased sensitivity to tyramine. Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of rasagiline tablets because of the potential for large increases in blood pressure including clinical syndromes referred to as hypertensive urgency, crisis, or emergency. Rasagiline tablets are a selective inhibitor of MAO-B at the recommended doses of 0.5 or 1 mg daily. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses.

5.2 Serotonin Syndrome

Serotonin syndrome has been reported with concomitant use of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a nonselective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl®) and rasagiline tablets. Serotonin syndrome has also been reported with concomitant use of rasagiline tablets with meperidine, tramadol, methadone, or propoxyphene. Rasagiline tablets are contraindicated for use with meperidine, tramadol, methadone, propoxyphene, and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors [see Contraindications (4) and Drug Interactions (7.1, 7.2, 7.3)].

In the postmarketing period, potentially life-threatening serotonin syndrome has been reported in patients treated with antidepressants concomitantly with rasagiline tablets. Concomitant use of rasagiline tablets with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended [see Drug Interactions (7.5)].

The symptoms of serotonin syndrome have included behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor). Serotonin syndrome can result in death.

Rasagiline tablets clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with rasagiline tablets, and the potential drug interaction between rasagiline tablets and antidepressants has not been studied systematically. Although a small number of rasagiline tablets-treated patients were concomitantly exposed to antidepressants (tricyclics n = 115; SSRIs n = 141), the exposure, both in dose and number of subjects, was not adequate to rule out the possibility of an untoward reaction from combining these agents. At least 14 days should elapse between discontinuation of rasagiline tablets and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. Because of the long half-lives of certain antidepressants (e.g., fluoxetine and its active metabolite), at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of rasagiline tablets [see Drug Interactions (7.5)].

5.3 Falling Asleep During Activities of Daily Living and Somnolence

It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should monitor patients for drowsiness or sleepiness, because some of the events occur well after initiation of treatment with dopaminergic medication. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Cases of patients treated with rasagiline tablets and other dopaminergic medications have reported falling asleep while engaged in activities of daily living including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on rasagiline tablets with other dopaminergic medications, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported more than 1-year after initiation of treatment.

In Study 3, somnolence was a common occurrence in patients receiving rasagiline tablets and was more frequent in patients with Parkinson’s disease receiving rasagiline tablets than in respective patients receiving placebo (6% rasagiline tablets compared to 4% Placebo) [see Adverse Reactions (6.1)].

Before initiating treatment with rasagiline tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with rasagiline tablets such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase rasagiline plasma levels (e.g., ciprofloxacin) [see Drug Interactions (7.6)]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), rasagiline tablets should ordinarily be discontinued. If a decision is made to continue these patients on rasagiline tablets, advise them to avoid driving and other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.4 Ciprofloxacin or Other CYP1A2 Inhibitors

Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of rasagiline tablets 0.5 mg once daily [see Dosage and Administration (2.2), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].

5.5 Hepatic Impairment

Rasagiline plasma concentration may increase in patients with hepatic impairment. Patients with mild hepatic impairment should be given the dose of rasagiline tablets 0.5 mg once daily. Rasagiline tablets should not be used in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

5.6 Hypotension/Orthostatic Hypotension

In Study 3, the incidence of orthostatic hypotension consisting of a systolic blood pressure decrease (≥ 30 mm Hg) or a diastolic blood pressure decrease (≥ 20 mm Hg) after standing was 13% with rasagiline tablets (1 mg/day) compared to 9% with placebo [see Adverse Reactions (6.1)].

At the 1 mg dose, the frequency of orthostatic hypotension (at any time during the study) was approximately 44% for rasagiline tablets vs 33% for placebo for mild to moderate systolic blood pressure decrements (≥ 20 mm Hg), 40% for rasagiline tablets vs 33% for placebo for mild to moderate diastolic blood pressure decrements (≥ 10 mm Hg), 7% for rasagiline tablets vs 3% for placebo for severe systolic blood pressure decrements (≥ 40 mm Hg), and 9% for rasagiline tablets vs 6% for placebo for severe diastolic blood pressure decrements (≥ 20 mm Hg). There was also an increased risk for some of these abnormalities at the lower 0.5 mg daily dose and for an individual patient having mild to moderate or severe orthostatic hypotension for both systolic and diastolic blood pressure.

In Study 2 where rasagiline tablets were given as an adjunct therapy in patients not taking concomitant levodopa, there were 5 reports of orthostatic hypotension in patients taking rasagiline tablets 1 mg (3.1%) and 1 report in patients taking placebo (0.6%) [see Adverse Reactions (6.1)].

Clinical trial data further suggest that orthostatic hypotension occurs most frequently in the first two months of rasagiline tablets treatment and tends to decrease over time.

Some patients treated with rasagiline tablets experienced a mildly increased risk for significant decreases in blood pressure unrelated to standing but while supine.

The risk for post-treatment hypotension (e.g., systolic < 90 or diastolic < 50 mm Hg) combined with a significant decrease from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for rasagiline tablets 1 mg (3.2%) compared to placebo (1.3%).

There was no clear increased risk for lowering of blood pressure or postural hypotension associated with rasagiline tablets 1 mg/day as monotherapy.

When used as an adjunct to levodopa, postural hypotension was also reported as an adverse reaction in approximately 6% of patients treated with rasagiline tablets 0.5 mg, 9% of patients treated with rasagiline tablets 1 mg and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with rasagiline tablets 1 mg/day, no patients treated with rasagiline tablets 0.5 mg/day and no placebo-treated patients.

5.7 Dyskinesia

When used as an adjunct to levodopa, rasagiline tablets may cause dyskinesia or potentiate dopaminergic side effects and exacerbate preexisting dyskinesia. In Study 3, the incidence of dyskinesia was 18% for patients treated with 0.5 mg or 1 mg rasagiline tablets as an adjunct to levodopa and 10% for patients treated with placebo as an adjunct to levodopa. Decreasing the dose of levodopa may mitigate this side effect [see Adverse Reactions (6.1)].

5.8 Hallucinations/Psychotic-Like Behavior

In the monotherapy study (Study 1), the incidence of hallucinations reported as an adverse event was 1.3% in patients treated with rasagiline tablets 1 mg and 0.7% in patients treated with placebo. In Study 1, the incidence of hallucinations reported as an adverse reaction and leading to drug discontinuation and premature withdrawal was 1.3% in patients treated with rasagiline tablets 1 mg and 0% in placebo-treated patients.

When studied as an adjunct therapy without levodopa (Study 2), hallucinations were reported as an adverse reaction in 1.2% of patients treated with 1 mg/day rasagiline tablets and 1.8% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from the clinical trial in 0.6% of patients treated with rasagiline tablets 1 mg/day and in none of the placebo-treated patients.

When studied as an adjunct to levodopa (Study 3), the incidence of hallucinations was approximately 5% in patients treated with rasagiline tablets 0.5 mg/day, 4% in patients treated with rasagiline tablets 1 mg/day, and 3% in patients treated with placebo. The incidence of hallucinations leading to drug discontinuation and premature withdrawal was about 1% in patients treated with 0.5 mg rasagiline tablets and 1 mg rasagiline tablets/day, and 0% in placebo-treated patients [see Adverse Reactions (6.1)].

Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with rasagiline tablets or after starting or increasing the dose of rasagiline tablets. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.

Patients should be informed of the possibility of developing hallucinations and instructed to report them to their healthcare provider promptly should they develop.

Patients with a major psychotic disorder should ordinarily not be treated with rasagiline tablets because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, many treatments for psychosis that decrease central dopaminergic tone may decrease the effectiveness of rasagiline tablets [see Drug Interactions (7.8)].

Consider dose reduction or stopping the medication if a patient develops hallucinations or psychotic like behaviors while taking rasagiline tablets.

5.9 Impulse Control/Compulsive Behaviors

Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including rasagiline tablets, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with rasagiline tablets. Consider dose reduction or stopping the medication if a patient develops such urges while taking rasagiline tablets.

5.10 Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the rates of adverse reactions observed in practice.

During the clinical development of rasagiline tablets, Parkinson’s disease patients received rasagiline tablets as initial monotherapy (Study 1) and as adjunct therapy (Study 2, Study 3, Study 4). As the populations in these studies differ, not only in the adjunct use of dopamine agonists or levodopa during rasagiline tablets treatment, but also in the severity and duration of their disease, the adverse reactions are presented separately for each study.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of rasagiline tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders: Melanoma

7.1 Meperidine

Serious, sometimes fatal reactions have been precipitated with concomitant use of meperidine (e.g., Demerol® and other tradenames) and MAO inhibitors including selective MAO-B inhibitors [see Contraindications (4)].

7.2 Dextromethorphan

The concomitant use of rasagiline tablets and dextromethorphan was not allowed in clinical studies. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Therefore, in view of rasagiline tablets’ MAO inhibitory activity, dextromethorphan is contraindicated for use with rasagiline tablets [see Contraindications (4)].

7.3 MAO Inhibitors

Rasagiline tablets are contraindicated for use with other MAO inhibitors because of the increased risk of nonselective MAO inhibition that may lead to a hypertensive crisis [see Contraindications (4)].

7.4 Sympathomimetic Medications

The concomitant use of rasagiline tablets and sympathomimetic medications was not allowed in clinical studies. Severe hypertensive reactions have followed the administration of sympathomimetics and nonselective MAO inhibitors. Hypertensive crisis has been reported in patients taking the recommended dose of rasagiline tablets and sympathomimetic medications. Severe hypertension has been reported in patients taking the recommended dose of rasagiline tablets and ophthalmic drops containing sympathomimetic medications.

Because rasagiline tablets are a selective MAOI, hypertensive reactions are not ordinarily expected with the concomitant use of sympathomimetic medications. Nevertheless, caution should be exercised when concomitantly using recommended doses of rasagiline tablets with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies.

7.5 Antidepressants

Concomitant use of rasagiline tablets with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic, or tetracyclic antidepressants) is not recommended [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Concomitant use of rasagiline tablets and MAO inhibitors is contraindicated [see Contraindications (4)].

7.6 Ciprofloxacin or Other CYP1A2 Inhibitors

Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. This could result in increased adverse events. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of rasagiline tablets 0.5 mg once daily [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

7.7 Tyramine/Rasagiline Interaction

MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a tyramine reaction with hypertension including clinical syndromes referred to as hypertensive urgency, crisis, or emergency. Foods and medications containing large amounts of exogenous amines (e.g., from fermented cheese, herring, over-the-counter cough/cold medications) may cause release of norepinephrine resulting in a rise in systemic blood pressure.

Results of a special tyramine challenge study indicate that rasagiline is selective for MAO-B at recommended doses and can be used without dietary tyramine restriction. However, certain foods may contain very high amounts (i.e., 150 mg or greater) of tyramine and could potentially cause a hypertensive reaction in individual patients taking rasagiline tablets due to increased sensitivity to tyramine. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses.

There were no cases of hypertensive crisis in the clinical development program associated with 1 mg daily rasagiline tablets treatment, in which most patients did not follow dietary tyramine restriction.

There have been postmarketing reports of patients who experienced significantly elevated blood pressure (including rare cases of hypertensive crisis) after ingestion of unknown amounts of tyramine-rich foods while taking recommended doses of rasagiline tablets. Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of rasagiline tablets [see Warnings and Precautions (5.1)].

7.8 Dopaminergic Antagonists

It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of rasagiline tablets.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Approximately half of patients in clinical trials were 65 years and over. There were no significant differences in the safety profile of the geriatric and nongeriatric patients.

8.6 Hepatic Impairment

Rasagiline plasma concentration may be increased in patients with mild (up to 2 fold, Child-Pugh score 5-6), moderate (up to 7 fold, Child-Pugh score 7-9), and severe (Child-Pugh score 10-15) hepatic impairment. Patients with mild hepatic impairment should not exceed a dose of 0.5 mg/day. Rasagiline tablets should not be used in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Dose adjustment of rasagiline tablets is not required for patients with mild or moderate renal impairment because rasagiline plasma concentrations are not increased in patients with moderate renal impairment. Rasagiline has not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

9.1 Controlled Substance

Rasagiline mesylate is not a controlled substance.

9.2 Abuse

Studies conducted in mice and rats did not reveal any potential for drug abuse and dependence. Clinical trials have not revealed any evidence of the potential for abuse, tolerance, or physical dependence; however, systematic studies in humans designed to evaluate these effects have not been performed.

9.3 Dependence

Studies conducted in mice and rats did not reveal any potential for drug abuse and dependence. Clinical trials have not revealed any evidence of the potential for abuse, tolerance, or physical dependence; however, systematic studies in humans designed to evaluate these effects have not been performed.

12.1 Mechanism of Action

Rasagiline tablets are a selective, irreversible MAO-B inhibitor indicated for the treatment of idiopathic Parkinson’s disease. The results of a clinical trial designed to examine the effects of rasagiline tablets on blood pressure when it is administered with increasing doses of tyramine indicates the functional selectivity can be incomplete when healthy subjects ingest large amounts of tyramine while receiving recommended doses of rasagiline tablets. The selectivity for inhibiting MAO-B diminishes in a dose-related manner.

MAO, a flavin-containing enzyme, is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. MAO-B is the major form in the human brain. In ex vivo animal studies in brain, liver, and intestinal tissues, rasagiline was shown to be a potent, irreversible monoamine oxidase type B (MAO-B) selective inhibitor. Rasagiline at the recommended therapeutic dose was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The precise mechanisms of action of rasagiline are unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline’s beneficial effects seen in models of dopaminergic motor dysfunction.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Rasagiline in the range of 1-6 mg demonstrated a more than proportional increase in AUC, while Cmax was dose proportional. Rasagiline mean steady-state half life is 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Monotherapy Use of Rasagiline Tablets

Study 1 was a double-blind, randomized, fixed-dose parallel group, 26-week study in early Parkinson’s disease patients not receiving any concomitant dopaminergic therapy at the start of the study. The majority of the patients were not treated with medications for Parkinson’s disease before receiving rasagiline tablets.

In Study 1, 404 patients were randomly assigned to receive placebo (138 patients), rasagiline tablets 1 mg/day (134 patients) or rasagiline tablets 2 mg/day (132 patients). Patients were not allowed to take levodopa, dopamine agonists, selegiline, or amantadine, but could take stable doses of anticholinergic medication, if necessary. The average Parkinson’s disease duration was approximately 1 year (range 0 to 11 years).

The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS), [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)]. The UPDRS is a multi-item rating scale that measures the ability of a patient to perform mental and motor tasks as well as activities of daily living. A reduction in the score represents improvement and a beneficial change from baseline appears as a negative number.

Rasagiline tablets (1 or 2 mg once daily) were superior to placebo on the primary measure of effectiveness in patients receiving six months of treatment and not on dopaminergic therapy. The effectiveness of rasagiline tablets 1 mg and 2 mg was comparable. Table 4 shows the results of Study 1. There were no differences in effectiveness based on age or gender between rasagiline tablets 1 mg/day and placebo.

14.2 Adjunct Use of Rasagiline Tablets

Study 2 was a double-blind, randomized, placebo-controlled, parallel group, 18-week study, investigating rasagiline tablets 1 mg as adjunct therapy to dopamine agonists without levodopa. Patients were on a stable dose of dopamine agonist (ropinirole, mean 8 mg/day or pramipexole, mean 1.5 mg/day) therapy for ≥ 30 days, but at doses not sufficient to control Parkinson’s disease symptoms.

In Study 2, 321 patients randomly received placebo (162 patients) or rasagiline tablets 1 mg/day (159 patients) and had a post-baseline assessment. The average Parkinson’s disease duration was approximately 2 years (range 0.1 to 14.5 years).

The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS) [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)].

In Study 2, rasagiline tablets 1 mg were superior to placebo on the primary measure of effectiveness (see Table 5).

Secondary outcome assessment of the individual subscales of the UPDRS indicates that the UPDRS Part III motor subscale was primarily responsible for the overall rasagiline tablets effect on the UPDRS score (see Table 6).

Study 3 and Study 4 were randomized, multinational trials conducted in more advanced Parkinson’s disease patients treated chronically with levodopa and experiencing motor fluctuations (including but not limited to, end of dose “wearing off,” sudden or random “off,” etc.). Study 3 was conducted in North America (U.S. and Canada) and compared rasagiline tablets 0.5 mg and 1 mg daily to placebo. Study 4 was conducted outside of North America in Europe, Argentina, and Israel, and compared rasagiline tablets 1 mg daily to placebo.

Patients had Parkinson’s disease for an average of 9 years (range 5 months to 33 years), had taken levodopa for an average of 8 years (range 5 months to 32 years), and had motor fluctuations for approximately 3 to 4 years (range 1 month to 23 years). Patients kept home Parkinson’s disease diaries just prior to baseline and at specified intervals during the trial. Diaries recorded one of the following four conditions for each half-hour interval over a 24-hour period: “ON” (period of relatively good function and mobility) as either “ON” with no dyskinesia or without troublesome dyskinesia, or “ON” with troublesome dyskinesia, “OFF” (period of relatively poor function and mobility) or asleep. “Troublesome” dyskinesia is defined as dyskinesia that interferes with the patient’s daily activity. All patients had inadequate control of their motor symptoms with motor fluctuations typical of advanced stage disease despite receiving levodopa/decarboxylase inhibitor. The average dose of levodopa taken with a decarboxylase inhibitor was approximately 700 to 800 mg (range 150 to 3000 mg/day). Patients continued their stable doses of additional anti-PD medications at entry into the trials. Approximately 65% of patients in both studies were also taking a dopamine agonist. In the North American study (Study 3), approximately 35% of patients took entacapone with levodopa/decarboxylase inhibitor. The majority of patients taking entacapone were also taking a dopamine agonist.

In Study 3 and Study 4, the primary measure of effectiveness was the change in the mean number of hours spent in the “OFF” state at baseline compared to the mean number of hours spent in the “OFF” state during the treatment period.

In Study 3, patients were randomly assigned to receive placebo (159 patients), rasagiline tablets 0.5 mg/day (164 patients), or rasagiline tablets 1 mg/day (149 patients) for 26 weeks. Patients averaged 6 hours daily in the “OFF” state at baseline as confirmed by home diaries.

In Study 4, patients were randomly assigned to receive placebo (229 patients), rasagiline tablets 1 mg/day (231 patients) or a COMT inhibitor (active comparator), taken along with scheduled doses of levodopa/decarboxylase inhibitor (227 patients) for 18 weeks. Patients averaged 5.6 hours daily in the “OFF” state at baseline as confirmed by home diaries.

In Study 3 and Study 4, rasagiline tablets 1 mg once daily reduced “OFF” time compared to placebo when added to levodopa in patients experiencing motor fluctuations (Tables 7 and 8). The lower dose (0.5 mg) of rasagiline tablets also significantly reduced “OFF” time (Table 7), but had a numerically smaller effect than the 1 mg dose of rasagiline tablets. In Study 4, the active comparator also reduced “OFF” time when compared to placebo.

In Study 3 and Study 4, dose reduction of levodopa was allowed within the first 6 weeks, if dopaminergic side effects developed including dyskinesia or hallucinations. In Study 3, the levodopa dose was reduced in 8% of patients in the placebo group and in 16% and 17% of patients in the 0.5 mg/day and 1 mg/day rasagiline tablets groups, respectively. When levodopa was reduced, the dose was reduced by 7%, 9%, and 13% in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In Study 4, levodopa dose reduction occurred in 6% of patients in the placebo group and in 9% in the rasagiline tablets 1 mg/day groups, respectively. When levodopa was reduced, it was reduced by 13% and 11% in the placebo and the rasagiline tablets groups, respectively.

There were no differences in effectiveness based on age or gender between rasagiline tablets 1 mg/day and placebo.

Several secondary outcome assessments in the two studies showed statistically significant improvements with rasagiline. These included effects on the activities of daily living (ADL) subscale of the UPDRS performed during an “OFF” period and the motor subscale of the UPDRS performed during an “ON” period. In both scales, a negative response represents improvement. Tables 9 and 10 show these results for Studies 3 and 4.