PRODUCT MONOGRAPH

PrAZILECT(r)

(rasagiline mesylate tablets)

mg and 1 mg tablets (as rasagiline mesylate)

Antiparkinson Agent

TEVA PHARMACEUTICAL Date of Revision: INDUSTRIES LTD. May 14, 2008 Netanya, 42080, Israel Manufactured for: TEVA NEUROSCIENCE Montreal, Quebec H3A 3L4 By: TEVA PHARMACEUTICAL INDUSTRIES, LTD. Kfar-Saba, 44102, Israel Distributed by: NOVOPHARM LTD. Toronto, Ontario, M1B 2K9 Control Number: 120131

PRODUCT MONOGRAPH

PrAZILECT(r)

(rasagiline mesylate tablets)

mg and 1 mg tablets (as rasagiline mesylate)

Therapeutic Classification

Antiparkinson Agent

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

AZILECT (rasagiline mesylate tablets) is an irreversible, monoamine oxidase inhibitor indicated for the treatment of idiopathic Parkinson's disease. AZILECT inhibits MAO type B, but adequate studies to establish whether rasagiline is selective for MAO type B (MAO-B) in humans have not yet been conducted. 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 dose at which rasagiline selectively inhibits only MAO-B (and not MAO-A) in humans and the sensitivity to tyramine during rasagiline treatment at doses higher than 1 mg have not been sufficiently characterized. (See PRECAUTIONS) 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.

Pharmacodynamics

Platelet MAO activity in clinical studies:

Studies in healthy subjects and in Parkinson's disease patients have shown that rasagiline inhibits platelet MAO-B irreversibly. The inhibition lasts at least 1 week after last dose. Almost 25-35 % MAO-B inhibition was achieved after a single rasagiline dose of 1 mg/day and more than 55% of MAO-B inhibition was achieved after a single rasagiline dose of 2 mg/day. Over 90% inhibition was achieved 3 days after rasagiline daily dosing at 2 mg/day and this inhibition level was maintained 3 days post-dose. Multiple doses of rasagiline of 0.5, 1 and 2 mg per day resulted in complete MAO-B inhibition.

Pharmacokinetics

Rasagiline's pharmacokinetics are linear with doses over the range of 1 -10 mg. Its 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. Absorption: Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 1 hour. The absolute bioavailability of rasagiline is about 36%. Food does not affect the Tmax of rasagiline, although Cmax and exposure (AUC) are decreased by approximately 60% and 20%, respectively, when the drug is taken with a high fat meal. Because AUC is not significantly affected, AZILECT can be administered with or without food (See DOSAGE AND ADMINISTRATION).

Distribution:

The mean volume of distribution at steady-state is 87 L indicating that the tissue binding of rasagiline is in excess of plasma protein binding. Plasma protein binding ranges from 88- 94% with mean extent of binding of 61-63% to human albumin over the concentration range of 1- 100 ng/mL.

Metabolism and Elimination: Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through two main pathways: N- dealkylation and/or hydroxylation to yield: 1-aminoindan (AI), 3-hydroxy-N-propargyl-1 aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). In vitro experiments indicate that both routes of rasagiline metabolism are dependent on cytochrome P450 (CYP) system, with CYP 1A2 being the major iso-enzyme involved in rasagiline metabolism. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.

Population pharmacokinetics

Hepatic Insufficiency: Following repeat dose administration (7 days) of rasagiline (1 mg/day) in subjects with mild hepatic impairment (Child-Pugh score 5-6), AUC and Cmax were increased by 2 fold and 1.4 fold, respectively, compared to healthy subjects. In subjects with moderate hepatic impairment (Child-Pugh score 7-9), AUC and Cmax were increased by 7 fold and 2 fold, respectively, compared to healthy subjects. (See WARNINGS, Hepatic Insufficiency and DOSAGE AND ADMINISTRATION, Patients with Hepatic Impairment)

Renal Insufficiency:

Conclusive data are not available for renally impaired patients. As unconjugated rasagiline is not excreted by the kidney, rasagiline can be given at usual doses in patients with mild renal impairment. Due to the absence of adequate safety data, rasagiline should not be administered to patients with moderate to severe renal impairment.

Geriatric:

Since age has little influence on rasagiline pharmacokinetics, it can be administered at the recommended dose in the elderly.

Pediatric:

AZILECT has not been investigated in patients below 18 years of age.

Gender:

The pharmacokinetic profile of rasagiline is similar in men and women

Drug-Drug Interactions:

Tyramine Effect

(See PRECAUTIONS, SYMPTOMS AND TREATMENT OF OVERDOSAGE, DOSAGE AND ADMINISTRATION and INFORMATION FOR THE PATIENT)

Levodopa:

Data from population pharmacokinetic studies comparing rasagiline clearance in the presence and absence of levodopa have given conflicting results. Although there may be some increase in rasagiline blood levels in the presence of levodopa, the effect is modest and rasagiline dosing need not be modified in the presence of levodopa.

Effect of other drugs on the metabolism of AZILECT: In vitro metabolism studies showed that CYP 1A2 was the major enzyme responsible for the metabolism of rasagiline. There is the potential for inhibitors of this enzyme to alter AZILECT clearance when co-administered. (See WARNINGS, Ciprofloxacin and Other CYP1A2 Inhibitors and DOSAGE AND ADMINISTRATION, Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors.)

Ciprofloxacin: When ciprofloxacin, an inhibitor of CYP 1A2, was administered to healthy volunteers (n=12) at 500 mg (BID) with 2 mg/day rasagiline, the AUC of rasagiline increased by 83% and there was no change in the elimination half life. (See WARNINGS, Ciprofloxacin and Other CYP1A2 Inhibitors and DOSAGE AND ADMINISTRATION, Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors.)

Theophylline:

Co-administration of rasagiline 1 mg/day and theophylline, a substrate of CYP 1A2, up to 500 mg twice daily to healthy subjects (n=24), did not affect the pharmacokinetics of either drug.

Antidepressants:

Severe CNS toxicity associated with hyperpyrexia and death has been reported with the combination of tricyclic or tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) and non-selective MAOIs or selective MAO-B inhibitors. Therefore, the coadministration of antidepressants with rasagiline is contraindicated (See CONTRAINDICATIONS).

Effect of AZILECT on other drugs: No additional in vivo trials have investigated the effect of AZILECT on other drugs metabolized by the cytochrome P450 enzyme system. In vitro, studies showed that rasagiline at a concentration of 1mg/ml (equivalent to a level that is 160 times the average Cmax ~ 5.9-8.5 ng/mL in Parkinson's disease patients after 1 mg rasagiline multiple dosing, did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A. These results indicate that rasagiline is unlikely to cause any clinically significant interference with substrates of these enzymes.

Clinical Trials

In phase II/III premarketing trials approximately 1361 patients received AZILECT with 771being treated for at least one year, approximately 361 patients treated for at least two years, and 245 receiving AZILECT for more than 3 years. The effectiveness of AZILECT for the treatment of Parkinson's disease was established in three 18- to 26-week, randomized, placebo-controlled trials. In one of these trials study TVP-1012/232 (TEMPO) AZILECT was given as initial monotherapy treatment and in the other two studies as adjunctive therapy to levodopa TVP-1012/133 (PRESTO) and TVP-1012/122 (LARGO).

Monotherapy Use of AZILECT

The monotherapy trial (TEMPO) was a double-blind, randomized, fixed-dose parallel group 26- week study in early Parkinson's disease patients not yet receiving any concomitant dopaminergic therapy at the start of the study. The majority of the patients were not treated with any anti- Parkinson's disease medication before receiving AZILECT treatment. The first phase was placebo-controlled in which 404 patients were randomly assigned to receive placebo (138 patients), AZILECT 1 mg/day (134 patients) or AZILECT 2 mg/day (132 patients). Patients were not allowed to take levodopa, dopamine agonists, selegiline or amantadine, but if necessary, could take stable doses of anticholinergic medication. The average Parkinson's disease duration was approximately 1 year (range 0 to 11 years). Patients completing the first 26 weeks or patients requiring additional anti-PD therapy could start the second phase of double-blind treatment in which all patients received AZILECT, 1 or 2 mg once daily. Three hundred eighty patients entered the second phase. Patients who received AZILECT in the first phase remained on their originally assigned dose. Patients who received placebo in the first phase were switched to AZILECT, 2 mg once daily. 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 (1 or 2 mg once daily) had a significant beneficial effect relative to placebo on the primary measure of effectiveness in patients receiving six months of treatment and not on dopaminergic therapy. Patients who received rasagiline had significantly less worsening in the UPDRS score, compared to those who received placebo. The effectiveness of rasagiline 1 mg and 2 mg was comparable. Table 1 displays the results of the monotherapy trial.

Table 1.

Parkinson's Disease Patients not on Dopaminergic Therapy (TEMPO)

For the comparison between rasagiline 1mg/day and placebo, no differences in effectiveness based on age or gender were detected. In addition in the TEMPO study the following secondary measurements of effectiveness were statistically significant and the effects of AZILECT 1 mg tablets over placebo are presented below: UPDRS ADL (Activities of Daily Living) subscale score (p=0.0003); UPDRS Motor subscale score (p<0.0001).

Adjunctive Use of AZILECT

Two multicenter, randomized, multinational trials were 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) Studies TVP-1012/133 (PRESTO) and TVP-1012/122 (LARGO). The first (PRESTO) was conducted in North America (U.S. and Canada) and compared two doses (0.5 mg and 1 mg daily) of rasagiline and placebo while the second (LARGO) was conducted outside of North America (several European countries, Argentina, Israel) and studied a single dose (1 mg daily) of rasagiline, a COMT inhibitor with each levodopa dose and placebo. Patients had had Parkinson's disease for an average of 9 years (range 5 months to 33 years), had been taking levodopa for an average of 8 years (range 5 months to 32 years), and had been experiencing motor fluctuations for approximately 3 to 4 years (range 1 month to 23 years). Patients kept home 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, "ON" with troublesome dyskinesia, "OFF" (period of relatively poor function and mobility) or asleep. "Troublesome" dyskinesia is defined as that which interferes with the patient's daily activity. All patients had been inadequately controlled and were experiencing motor fluctuations typical of advanced stage disease despite receiving levodopa/decarboxylase inhibitor. The average dose of levodopa/decarboxylase inhibitor was approximately 700 to 800 mg (range 150 to 3000 mg/day). Patients were also allowed to take stable doses of additional anti-PD medications at entry into the trials. In both trials, approximately 65% of patients were on dopamine agonists and in the North American study (PRESTO) approximately 35% were on entacapone. The majority of patients taking entacapone were taking a dopamine agonist as well. In both trials the primary measure of effectiveness was the change in the mean number of hours that were spent in the "OFF" state at baseline compared to the mean number of hours that were spent in the "OFF" state during the treatment period. Secondary measures of effectiveness included global assessments of improvement by the examiner, ADL subscale scores when Off and UPDRS motor while ON. A reduction in the UPDRS score represents improvement and a beneficial change from baseline appears as a negative number. PRESTO was a double-blind, randomized, fixed-dose parallel group trial conducted in 472 levodopa-treated Parkinson's disease patients who were experiencing motor fluctuations. Patients were randomly assigned to receive placebo (159 patients), AZILECT 0.5 mg/day (164 patients), or AZILECT 1 mg/day (149 patients), and were treated for 26 weeks. Patients averaged approximately 6 hours daily in the "OFF" state at baseline, as confirmed by home diaries. LARGO was a double-blind, randomized, parallel group trial conducted in 687 levodopa-treated Parkinson's disease patients who were experiencing motor fluctuations. Patients were randomly assigned to receive placebo (229 patients), AZILECT 1 mg/day (231 patients) or an active comparator, a COMT inhibitor taken along with scheduled doses of levodopa/decarboxylase inhibitor (227 patients). Patients were treated for 18 weeks. Patients averaged approximately 5.6 hours daily in the "OFF" state at baseline as confirmed by home diaries. In both studies rasagiline 1 mg once daily reduced "OFF" time compared to placebo when added to levodopa in patients experiencing motor fluctuations (Tables 2 and 3). The lower dose (0.5 mg) of rasagiline also significantly reduced "OFF" time (Table 2), but had a numerically smaller effect than the 1mg dose of rasagiline. In LARGO, the active comparator also reduced "OFF" time when compared to placebo.

Table 2.

Parkinson's Disease Patients Receiving AZILECT as Adjunct Therapy (PRESTO)

Table 3.

Parkinson's Disease Patients Receiving AZILECT as Adjunct Therapy (LARGO)

In both studies, dosage reduction of levodopa was allowed within the first 6 weeks if dopaminergic side effects, including dyskinesia and hallucinations, emerged. In PRESTO, levodopa dosage reduction occurred in 8 % of patients in the placebo group and in 16 % and 17 % of patients in the mg/day and 1 mg/day rasagiline groups, respectively. In those patients who had levodopa dosage reduced, the dose was reduced on average by about 7 %, 9%, and 13 % in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In LARGO, levodopa dosage reduction occurred in 6 % of patients in the placebo group and in 9 % in the rasagiline 1 mg/day group. In patients who had their levodopa dosage reduced, the dose was reduced on average by about 13% and 11 % in the placebo and the rasagiline groups, respectively. For the comparison between rasagiline 1mg/day and placebo in both studies, no differences in effectiveness based on age or gender were detected. 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 as performed during an "ON" period. In both scales, a negative response represents improvement. Tables 4 and 5 show these results for PRESTO and LARGO.

Table 4.

Secondary Measures of Effectiveness (PRESTO)

Table 5.

Secondary Measures of Effectiveness (LARGO)

CONTRAINDICATIONS

Meperidine and Other Analgesics:

AZILECT is contraindicated for use with meperidine. Serious reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors. These reactions have been characterized by coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse and death. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with meperidine.

For similar reasons, AZILECT should not be administered with the analgesic agents tramadol, methadone, and propoxyphene.

Other Drugs:

AZILECT should not be used with the antitussive agent dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. AZILECT is also contraindicated for use with St. John's wort, and cyclobenzaprine (a tricyclic muscle relaxant).

Sympathomimetic Amines:

Like other MAOIs, AZILECT is contraindicated for use with sympathomimetic amines, including amphetamines as well as cold products and weight-reducing preparations that contain vasoconstrictors (e.g., pseudoephedrine, phenylephrine and ephedrine).

Severe hypertensive reactions have followed the administrations of sympathomimetics and non- selective MAO inhibitors. At least one case of hypertensive crisis has been reported in a patient taking the recommended doses of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine).

Antidepressants:

AZILECT should not be administered along with antidepressants. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with a tricyclic, tetracyclic, SSRI, or SNRI antidepressant. Similarly, at least 14 days should elapse after discontinuing treatment with a tricyclic, tetracyclic, SSRI, or SNRI antidepressant before starting AZILECT. Because of the long half-lives of 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 AZILECT. (See WARNINGS)

MAO inhibitors:

AZILECT should not be administered along with other MAO inhibitors because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with MAO inhibitors.

Surgery:

As with other MAOIs, patients taking AZILECT should not undergo elective surgery requiring general anesthesia. Also, they should not be given local anesthesia containing cocaine or sympathomimetic vasoconstrictors. AZILECT should be discontinued at least 14 days prior to elective surgery. If surgery is necessary sooner, benzodiazepines, mivacurium, fentanyl, morphine, and codeine may be used cautiously.

Pheochromocytoma

: As with other MAOIs, AZILECT is contraindicated in patients with

pheochromocytoma.

WARNINGS

Antidepressants:

Severe CNS toxicity associated with hyperpyrexia and death has been reported with the combination of tricyclic or tetracyclic antidepressants, non-selective MAOIs (NARDIL, PARNATE) including the reversible MAOI, moclobemide and a selective MAO-B inhibitor, selegiline. These adverse events have included behavioral and mental status changes, diaphoresis, muscular rigidity, hypertension, syncope and death.

Serious, sometimes fatal, reactions with signs and symptoms including hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuations, and mental status changes progressing to extreme agitation, delirium, and coma have been reported in patients receiving a combination of selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (PROZAC), fluvoxamine (LUVOX) sertraline (ZOLOFT), and paroxetine (PAXIL), non-selective MAOIs, including the reversible MAOI moclobemide, or the selective MAO-B inhibitor selegiline. Similar reactions have been reported with serotonin-norepinephrine reuptake inhibitors (SNRIs) At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with a tricyclic, tetracyclic, SSRI, or SNRI antidepressant. Similarly, at least 14 days should elapse after discontinuing treatment with a tricyclic, tetracyclic, SSRI, or SNRI antidepressant before starting AZILECT. Because of the long half-lives of 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 AZILECT. (See CONTRAINDICATIONS)

Ciprofloxacin and Other CYP1A2 Inhibitors: Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. (See ACTION and CLINICAL PHARMACOLOGY, Drug-Drug Interactions and DOSAGE AND ADMINISTRATION, Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors.)

Hepatic Insufficiency: AZILECT plasma concentration may increase 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 hepatic Child-Pugh score 10-15) impairment. Patients with mild hepatic impairment should be given the dose of 0.5 mg/day. AZILECT should not be used in patients with moderate or severe hepatic impairment. (See ACTION AND CLINICAL PHARMACOLOGY, Population pharmacokinetics).

PRECAUTIONS

General

Tyramine/rasagiline interaction:

Rasagiline should not be used at daily doses exceeding the maximum recommended (1 mg/day) because of the risks associated with nonselective inhibition of MAO. Adequate studies above this dose have not been conducted. Therefore, if rasagiline is to be used without restrictions being placed on diet and concomitant drug use, it is critical to adhere to this maximum dose.

Melanoma:

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general

population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Azilect for any indication. Ideally periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).

Dyskinesia Due to Levodopa Treatment:

When used as an adjunct to levodopa AZILECT may potentiate dopaminergic side effects and exacerbate pre-existing dyskinesia (treatment-emergent dyskinesia occurred in about 18% of patients treated with 0.5 mg or 1 mg rasagiline as an adjunct to levodopa and 10% of patients who received placebo as an adjunct to levodopa). Decreasing the dose of levodopa may ameliorate this side effect.

Postural Hypotension

: When used as monotherapy, postural hypotension was reported in approximately 3% of patients treated with 1 mg rasagiline and 5% of patients treated with placebo. In the monotherapy trial, postural hypotension did not lead to drug discontinuation and premature withdrawal in the rasagiline treated patients or the placebo treated patients.

When used as an adjunct to levodopa, postural hypotension was reported in approximately 6% of patients treated with 0.5 mg rasagiline, 9% of patients treated with 1 mg rasagiline 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 1 mg/day, no patients treated with rasagiline 0.5 mg/day and no placebo-treated patients. Clinical trial data suggest that postural hypotension occurs most frequently in the first two

Hallucinations:

In the monotherapy study, hallucinations were reported as an adverse event in 1.3% of patients treated with 1 mg rasagiline and in 0.7% of patients treated with placebo. In the monotherapy trial, hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 1.3% of the 1 mg rasagiline treated patients and in none of the placebo treated patients.

When used as an adjunct to levodopa, hallucinations were reported as an adverse event in approximately 5% of patients treated with 0.5 mg/day, 4% of patients treated with 1 mg/day rasagiline and 3% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of patients treated with 0.5 mg/day or 1 mg/day and none of the placebo treated patients. Patients should be cautioned of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop.

Information for Patients

The risk of exceeding the recommended daily dose (1 mg/day) should be explained. The explanation should describe the signs and symptoms associated with MAOI induced hypertensive reactions. Patients should be urged to immediately report any severe headache or other atypical or unusual symptoms not previously experienced. Patients should be advised to inform their physician if they are taking, or planning to take, any prescription or over-the-counter drugs especially with antidepressants and over-the-counter cold medications since there is a potential for interaction with AZILECT. Patients should not use Patients taking AZILECT as adjunct to levodopa should be advised there is the possibility of increased dyskinesia and postural hypotension. Patients are advised to monitor for melanomas frequently and on a regular basis. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists). Patients should be instructed to take AZILECT as prescribed. If a dose is missed the next dose should be taken at the usual time on the following day. The patient should not double-up the dose of AZILECT.

Drug Interactions

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)

Dextromethorphan: The concomitant use of AZILECT 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 AZILECT's MAO inhibitory activity, dextromethorphan should not be used concomitantly with AZILECT. (See CONTRAINDICATIONS)

Sympathomimetic medications:

The concomitant use of AZILECT and sympathomimetic medications was not allowed in clinical studies. Severe hypertensive reactions have followed the

administration of sympathomimetics and non-selective MAO inhibitors. One case of hypertensive crisis has been reported in a patient taking the recommended doses of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine). Therefore, in view of AZILECT's MAO inhibitory activity, AZILECT should not be used concomitantly with sympathomimetics including nasal and oral decongestants and cold remedies. (See CONTRAINDICATIONS).

MAO inhibitors: AZILECT should not be administered along with other MAO inhibitors, including reversible MAOI (moclobemide) and selective MAO-B inhibitors (selegiline) because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis. (See CONTRAINDICATIONS.)

Selective serotonin reuptake inhibitors (SSRIs), tricyclic and tetracyclic antidepressants:

Concomitant use of SSRI, tricyclic, and tetracyclic antidepressants with AZILECT is contraindicated (See CONTRAINDICATIONS.)

Levodopa/carbidopa: (See ACTION AND CLINICAL PHARMACOLOGY, Drug-Drug Interactions PRECAUTIONS, General, Dyskinesias Due to Levodopa Treatment.)

Ciprofloxacin: and 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. (See ACTION AND CLINICAL PHARMACOLOGY, Drug-Drug Interactions and WARNINGS, Ciprofloxacin and Other CYP1A2 Inhibitors.)

Laboratory Tests

No specific laboratory tests are necessary for the management of patients on AZILECT.

Use in Pregnancy

Reproductive studies conducted with rasagiline in animals did not reveal any negative effect at doses much higher than those used in the clinical studies. However, there are no adequate and well- controlled studies of rasagiline in pregnant women. Because animal reproduction studies are not always predictive of human response, AZILECT should be used during pregnancy only if clearly needed.

Nursing Mothers

Experimental data indicated that rasagiline inhibits prolactin secretion and, thus, may inhibit lactation. It is not known whether rasagiline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AZILECT is administered to a nursing woman. The safety and effectiveness of AZILECT in patients below 18 years of age have not been established.

Use in the Elderly

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 non-geriatric patients.

Renal Insufficiency:

Conclusive data are not available for renally impaired patients. As unconjugated rasagiline is not excreted by the kidney, rasagiline can be given at usual doses in patients with mild renal impairment. Due to the absence of adequate safety data, rasagiline should not be administered to patients with moderate to severe renal impairment.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No cases of AZILECT (rasagiline mesylate tablets) overdose were reported in clinical trials. Rasagiline was well tolerated in a single-dose study in healthy volunteers receiving 20 mg/day and in a ten-day study in healthy volunteers receiving 10 mg/day. Adverse events were mild or moderate. In a dose escalation study in patients on chronic levodopa therapy treated with 10 mg of rasagiline there were three reports of cardiovascular side effects (including hypertension and postural hypotension) which resolved following treatment discontinuation. Symptoms of overdosage, although never observed with rasagiline during clinical development, may resemble those observed with non-selective MAO inhibitors. Although no cases of overdose have been observed with rasagiline, the following description of presenting symptoms and clinical course is based upon overdose descriptions of non-selective MAO inhibitors. Characteristically, signs and symptoms of non-selective MAOI overdose may not appear immediately. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur. Importantly, the peak intensity of the syndrome may not be reached for upwards of a day following the overdose. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring for a period of at least two days following the ingestion of such drugs in overdose, is strongly recommended. The clinical picture of MAOI overdose varies considerably; its severity may be a function of the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved. Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. There is no specific antidote for rasagiline overdose. The following suggestions are offered based upon the assumption that rasagiline overdose may be modeled after non-selective MAO inhibitor poisoning. Treatment of overdose with non-selective MAO inhibitors is symptomatic and supportive. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential. A poison control center should be called for the most current treatment guidelines.

DOSAGE AND ADMINISTRATION

Dosing Considerations:

• The recommended and maximum dose in both monotherapy and adjunct therapy is 1 mg once daily.

• AZILECT can be taken with or without food.

There is no evidence that additional benefit will be obtained from the administration of doses higher than that recommended. Furthermore, higher doses will likely result in a loss of selectivity of rasagiline towards MAO-B with an increase in the inhibition of MAO-A. There is an increased risk of adverse reactions with higher doses as well as an increased risk of hypertensive episode ("cheese reaction")

Monotherapy

The recommended AZILECT dose for the treatment of Parkinson's disease patients is 1 mg administered once daily.

Adjunctive Therapy

The dosage of AZILECT shown to be effective in controlled clinical trials for adjunct therapy was 0.5 - 1 mg once daily. The recommended initial dose is 0.5 mg administered once daily. If a sufficient clinical response is not achieved, the dose may be increased to 1 mg administered once daily.

Change of levodopa dose in adjunct therapy:

When AZILECT is used in combination with levodopa a reduction of the levodopa dosage may be considered based upon individual response. During the controlled trials of AZILECT as adjunct therapy to levodopa, levodopa dosage was reduced in some patients. In clinical studies, dosage reduction of levodopa was allowed within the first 6 weeks if dopaminergic side effects, including dyskinesia and hallucinations, emerged. In the PRESTO study levodopa dosage reduction occurred 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 groups, respectively. In those patients who had levodopa dosage reduced, the dose was reduced on average by about 7 %, 9%, and 13 % in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In the LARGO study levodopa dosage reduction occurred in 6 % of patients in the placebo group and in 9 % in the rasagiline 1 mg/day group. In patients who had their levodopa dosage reduced, the dose was reduced on average by about 13% and 11 % in the placebo and the rasagiline groups, respectively.

Patients with Hepatic Impairment: (, Population pharmacokinetics, Hepatic Insufficiency Hepatic Insufficiency)

AZILECT plasma concentration will increase in patients with hepatic impairment. Patients with mild hepatic impairment AZILECT should use 0.5 mg daily of AZILECT. AZILECT should not be used in patients with moderate to severe hepatic impairment.

See ACTION AND CLINICAL PHARMACOLOGY

and WARNINGS,

Patients with Renal Impairment:

Conclusive data are not available for renally impaired patients. As unconjugated rasagiline is not excreted by the kidney, rasagiline can be given at usual doses in patients with mild renal impairment. Due to the absence of adequate safety data, rasagiline should not be administered to patients with moderate to severe renal impairment.

Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors: Rasagiline plasma concentrations are expected to double in patients taking concomitant ciprofloxacin and other CYP1A2 inhibitors. Therefore, patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should use 0.5 mg daily of AZILECT (See ACTION AND CLINICAL PHARMACOLOGY, Drug-Drug Interaction Ciprofloxacin and Effect of other drugs on the metabolism of AZILECT; and WARNINGS, Ciprofloxacin and Other CYP1A2 Inhibitors.)

PHARMACEUTICAL INFORMATION

Drug Substance:

Description: Rasagiline mesylate is a propargyl amine-based drug indicated for the treatment of idiopathic Parkinson's disease. Common Name: Rasagiline mesylate Chemical Name: N-Propargyl-1(R)-aminoindan mesylate Chemical Abstract Service (CAS) Name: 1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-, (1R)-, methanesulfonate Structural Formula: (C12H13N).CH4SO3

. CH SO H

3 3

N

H CH

Molecular Weight: 267.34 Physical Form: White to off-white powder Solubility: Freely soluble in water or ethanol and sparingly soluble in isopropanol

Composition

Each 0.5 mg and 1 mg AZILECT tablet contains 0.5 mg and 1mg, respectively, of rasagiline, as mesylate. Each AZILECT tablet also contains the following inactive ingredients: mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid and talc.

Stability and Storage Recommendations

Storage: Store at 25degC (77degF) with excursions permitted to 15deg-30degC (59deg-86degF)

AVAILABILITY OF DOSAGE FORMS

AZILECT (rasagiline mesylate tablets) 0.5 mg are white to off-white, round, flat, beveled tablets, debossed with "GIL" and "0.5" below on one side and plain on the other. AZILECT (rasagiline mesylate tablets) 1 mg are white to off-white, round, flat, beveled tablets, debossed with "GIL" and "1" below on one side and plain on the other. They are supplied as follows: Bottles of 30 tablets

Information for the Patient

PrAZILECT(r)

mg and 1 mg tablets (as rasagiline mesylate)

Your physician has prescribed AZILECT (rasagiline mesylate) 0.5 mg or 1 mg tablets, a drug that has been shown to be effective in treating of the signs and symptoms of Parkinson's disease as initial therapy for early disease and as add-on therapy to levodopa in later stages of the disease. Before you begin using AZILECT, make sure you understand all the information provided about its possible benefits and risks. If you do not understand any of the information provided, contact your doctor for further clarification.

WHAT AZILECT IS AND WHAT IT IS USED FOR

AZILECT tablets are white to off-white, round, flat, bevelled tablets, marked with "GIL 0.5" on one side and plain on the other side for the 0.5 mg tablet or "GIL 1" on one side and plain on the other side for the 1 mg tablet. AZILECT is used to treat the signs and symptoms of Parkinson's disease as monotherapy (without levodopa) or as adjunct therapy (with levodopa). Parkinson's disease is a disorder of the central nervous system caused by a lack of dopamine - a substance in the brain used to send messages to your muscles to make them move. AZILECT belongs to a class of drugs called monoamine oxidase B inhibitors. AZILECT works by blocking the breakdown of dopamine in the brain.

DO NOT TAKE AZILECT IF

Do not use AZILECT if you:

• have moderate-to severe liver disease

• have pheochromocytoma (a type of tumour)

• plan to undergo elective surgery requiring general anaesthesia. Do not undergo elective surgery requiring general anaesthesia while on AZILECT. You should discontinue AZILECT at least 14 days prior to elective surgery. If surgery is necessary sooner, benzodiazepines, mivacurium, fentanyl, morphine, and codeine may be used cautiously.

Also, do not use AZILECT if you are taking any of the following medications: Antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs), SNRIs, tricyclic or tetracyclic antidepressants [e.g. Prozac (fluoxetine), Luvox (fluvoxamine) Zoloft (sertraline), Paxil (paroxetine), and Remeron (mirtazapine)] Sympathomimetic amines including amphetamines, cold medications, and weight- reducing products that contain vasoconstrictors (e.g., pseudoephedrine, phenylephrine and ephedrine) Cyclobenzaprine (a tricyclic muscle relaxant) Demerol (meperidine, pethidine) Dextromethorphan (an over-the-counter cough suppressant) MAO inhibitors for the treatment of Parkinson's disease or for any other indication Pain medications (notably tramadol, methadone, and propoxyphene) St. John's Wort Do not use AZILECT at the same time, or within 2 weeks before or after most antidepressants. Wait at least 5 weeks after stopping fluoxetine treatment before starting treatment with AZILECT

BEFORE YOU USE AZILECT

Before you use AZILECT, tell your doctor if you:

• are also taking levodopa, as there is the possibility of increased difficulty with movement. Your doctor may lower the dose of your levodopa therapy.

• have mild liver disease. Your dose may be reduced to 0.5 mg/day.

• are under the age of 18.

• are pregnant or planning to become pregnant. AZILECT should be used during pregnancy only if clearly needed.

• are breast-feeding

AZILECT may be taken if you have mild kidney disease but should not be taken if you have moderate to severe kidney impairment.

INTERACTIONS WITH THIS MEDICATION

See the DO NOT TAKE AZILECT section for important safety information about drugs not to use at the same time as AZILECT. Please ask your doctor or pharmacist for advice if you are taking or have recently taken any other medicines, even those obtained without a prescription. AZILECT may interact with the following medications or you might require a dose adjustment:

• Antidepressants

• Ciprofloxacin (an antibiotic) or other CYP1A2 inhibitors - if you take the antibiotic ciprofloxacin or other CYP1A2 inhibitors you should use 0.5 mg daily of AZILECT.

• Demerol (meperidine) or some other pain medications

• Dextromethorphan (an over-the-counter anti-cough drug)

• Levodopa - levodopa dose may be reduced

• Other MAOIs (monoamine oxidase inhibitors)

• Sympathomimetic amines including amphetamines, some decongestants, cold remedies, and weight loss products

HOW TO TAKE AZILECT

Take AZILECT exactly as instructed by your doctor. You should talk with your doctor or pharmacist if you are unsure. The recommended dose of AZILECT is 0.5 mg or 1 mg taken orally once daily either with or without food. Your doctor will determine which dose is appropriate for you. Do not take more then the maximum recommended daily dose of 1 mg. Taking more than 1 mg may cause serious side effects which could include a severe headache, seizures, and a sudden rise in blood pressure. Should you experience these or any other unusual symptoms you have not had before, call your doctor immediately.

If you take more AZILECT than you should:

If you think that you may have taken too many AZILECT tablets, contact your doctor or pharmacist immediately. Take the AZILECT carton/bottle with you to show the doctor or pharmacist.

If you forget to take AZILECT:

If you have forgotten to take a dose of AZILECT take the next dose at the usual time. Do not take a double dose to make up for the one you missed. Like all medicines, AZILECT can have side effects. The most commonly observed side effects that occurred in patients receiving AZILECT as monotherapy in placebo controlled clinical trials were: flu like symptoms, joint pain, depression, indigestion and falls. In patients receiving AZILECT as adjunct to levodopa therapy the most common side effects in placebo controlled clinical trials were: lack of coordination, accidental injury, weight loss, posture-dependant low blood pressure, vomiting, loss of appetite, joint pain, abdominal pain, nausea, constipation, dry mouth, rash, bruising, trouble sleeping, and abnormal skin sensation. Studies have shown that patients with Parkinson's disease have a higher risk of developing skin cancer than the general population, although it is unclear whether increased risk is due to Parkinson's disease itself or to drugs used to treat Parkinson's disease. Nevertheless you should examine your skin regularly to check for any unusual growth or discoloration. Ask your doctor if you are unsure what to look for. Ideally, periodic skin examinations should be performed by a dermatologist. AZILECT may cause hallucinations. Tell your doctor immediately if this happens to you while taking AZILECT. Taking more than 1 mg may cause serious side effects which could include a severe headache, seizures, and a sudden rise in blood pressure. Should you experience these or any other unusual symptoms you have not had before or not mentioned here, contact your doctor or pharmacist immediately.

WHAT DOES AZILECT CONTAIN

The active substance is rasagiline. Each tablet contains 0.5 mg or 1 mg rasagiline (as mesylate). The other non-medicinal ingredients are mannitol, colloidal anhydrous silica, maize starch, pregelatinised maize starch, stearic acid, talc.

STORING AZILECT

Keep out of the reach and sight of children. Store at room temperature (15-30o C). TEVA NEUROSCIENCE Montreal, Quebec H3A 3L4 1-866-530-6065 Last revision - May, 2008

PHARMACOLOGY

Rasagiline has been developed as the single (R)-isomer, which is three orders of magnitude more potent than the (S)-isomer, as a non-reversible inhibitor of MAO-B. It has been shown that there is no bioconversion of the isomers under in vivo exposure conditions in human plasma or during storage. The primary pharmacodynamic action of rasagiline is selective inhibition of monoamine oxidase type B (MAO-B). MAO-B inhibition elicits additional primary pharmacodynamic effects due to elevation of brain monoamine levels and dopamine in particular. These include protection against MPTP-induced neurotoxicity and possible amelioration in the performance of motor tasks and of cognition that had been impaired by neural injury. Apart from MAO inhibitory activity, rasagiline exhibited notable neuroprotective potency in in vitro and in vivo neurodegeneration models. This neuroprotective activity exhibited by rasagiline is considered as a secondary pharmacodynamic effect. Collectively, these pharmacological effects of rasagiline are suggested to underlie its beneficial activity in PD patients. Rasagiline is a potent, irreversible MAO-B selective inhibitor that effectively crosses the blood- brain barrier after oral administration and retains its MAO-B inhibitory activity after repeated dosing with IC50 values for human and rat brain of 2.5-20 nM. In vivo selective inhibition of brain MAO-B was confirmed in rats, mice, dogs and common marmosets. The daily oral dose (0.05 mg/kg/day) required to inhibit rat brain MAO-B activity by more than 90% is 1/10th of the dose of selegiline required to elicit the same effect. The higher MAO-B inhibitory potency of rasagiline as compared with selegiline was also demonstrated in the mouse MPTP-induced neurotoxicity model. Rasagiline selectivity for MAO-B inhibition upon repeated treatment is reflected in the high ED50 ratios (MAO- A)/(MAO-B) of 45 and 77 for rat brain and liver, respectively.

In vivo

microdialysis in rats confirmed that extracellular striatal dopamine is elevated, but without concomitant decreases in dopamine metabolites, after repeated oral administration of doses of rasagiline selective for MAO-B inhibition. Restoration of normal motor activity, after acute administration of rasagiline, was demonstrated in animal models of haloperidol or a-MpT-induced dopaminergic dysfunction. Chronically administered rasagiline (1-4 months) exhibits beneficial effects in models of hypoxia-induced motor dysfunction and cognitive deficits. Selegiline, by comparison whilst showing activity in some motor dysfunction models, had no activity in models of cognitive impairment.

The beneficial effects of chronically administered rasagiline may involve, in addition to MAO-B inhibition, a neuroprotective action. Rasagiline increased the survival of primary neurons and neuron-like cell lines. The in vitro neuroprotective activity of rasagiline was confirmed using several in vivo models of neuronal insult. The S-enantiomer of rasagiline, while inactive against MAO-B, exhibited an almost equivalent neuroprotective effect. Thus, it is suggested that the neuroprotective properties of rasagiline are not mediated by MAO inhibition. Selegiline has a lesser effect in the same systems and moreover, unlike rasagiline, produces a neurotoxic metabolite (L- metamphetamine). It has been shown that rasagiline has no effect on the cardiovascular system in the dog and rat at doses that are at least 10-fold higher than the clinical dose of 1 mg/day in patients. An Irwin screen in rats did not reveal any potential for unwanted pharmacological actions on the central nervous system. No respiratory adverse events were detected in any of the dog telemetry study, in repeated dose toxicology studies and in clinical studies (Phases I, II and III). As rasagiline may also be used as adjunctive therapy with levodopa, the effect of rasagiline on the levodopa pressor response was evaluated. It was shown that rasagiline did not potentiate the hypotensive effect of levodopa/carbidopa, when the compounds were co-administered repeatedly. There was no manifestation of the tyramine pressor response in rats given rasagiline at doses of up to 0.5 mg/kg/day (p.o.) for 21 days.

Pharmacokinetics

Absolute bioavailability, derived from comparison of AUC values for oral and intravenous dosing, can be estimated as 53-69% in rats and 13-22% in dogs. In rats and dogs, intravenously administered rasagiline is rapidly cleared at rates that exceed plasma flow through the liver and kidneys indicating extra-hepatic and extra-renal clearance. The volume of distribution exceeds that of the total body water indicating preferential localisation in tissues other than blood. Oral studies with 14C-rasagiline confirmed the rapid clearance of unchanged drug from the systemic circulation and the longer persistence of derived components. In rats given a single oral dose (0.37 mg/kg) of 14C-rasagiline mesylate less than 20% of the dose remained in the gastro-intestinal tract at 0.25 and 0.5 hours, plasma radioactivity was maximal at 0.25 hours declining thereafter with a terminal half-life of 61 hours. Plasma concentrations of unchanged drug declined with a terminal half-life of ca. 1 hour indicating an extensive first pass metabolism effect. In mice unchanged drug respectively accounted for 12 and 22% of the plasma radioactivity after oral doses of 14C-rasagiline at 1 and 45 mg/kg. In rats the amount of unchanged drug at 0.25 hours after an oral dose (0.37 mg/kg) of 14C-rasagiline accounted for ca. 10% of the plasma radioactivity. In the dog unchanged drug respectively accounts for 4.8% and 1.3% of the administered radioactivity at 1 and 2 hours after an oral dose of 14C-rasagiline at 1 mg/kg. The tissue distribution of 14C-rasagiline (0.37 mg/kg) was studied in albino and pigmented rats. Tissue radioactivity peaked between 0.25 and 0.5 hours, except for large intestine, urinary bladder and Lacrimal glands (about 4 hours). The tissue: whole blood ratios exceeded unity, and uptake was highest in liver. The high tissue:whole blood ratios were consistent with the high volume of distribution. Uptake was higher and persisted for longer in the eyes and skin of pigmented rats and there was autoradiographic evidence of persistence of radioactivity in the arterial walls at 24 hours. In vitro plasma protein binding varied between 70.7% and 75.2% for mice, 75.2% to 81.3% for rats and 80.9% and 88.9% for dogs. On the other hand, ex vivo binding to plasma proteins in dogs amounted to 17% at 1 and 2 hours, 28% at 4 hours and 44% at 8 hours after a single oral dose of

C-rasagiline.

The biotransformation of rasagiline was investigated using microsomal preparations from mice, rats, dogs and humans and plasma and urinary metabolites were profiled after in vivo dosing of mice, rats and dogs. Profiling of faecal metabolites was not undertaken because of the predominance of the urinary route of excretion in all species. Qualitatively similar metabolic profiles were established for mice, rats, dogs and humans. It is proposed that the parent molecule (PAI) undergoes N-dealkylation to form AI (aminoindan) and hydroxylation to form 3-hydroxy-N-propargyl-1-aminoindan (3-OH- PAI). There is also minor oxidative deamination to indanone. AI and 3-OH-PAI undergo further hydroxylation and/or N-dealkylation to form 3-OH-AI, 3-keto-PAI and 3-keto-AI and indanone undergoes further reduction to indanol. There is also conjugation of PAI and its metabolites with sulphate and/or glucuronic acid as well as N-acetylation. The metabolism of PAI appears to be CYP 450 dependent. The data generated permit qualitative comparison of the metabolite profile in plasma and semi-quantitative comparisons of the urinary metabolite profiles in mice, rats, dogs and humans. The semi-quantitative comparison of urinary metabolites is tabulated below:

Table 8.

Semi-Quantitative Comparison of Urine Metabolites in Different Species (% of administered dose in urine collected 0 - 48 hours post dose)

1 pooled urine samples from 6 healthy volunteers, that were treated with a single oral dose of 2 mg 14C-rasagiline mesylate (free base equivalent).

1. Enzymatic hydrolysis of conjugated metabolites was performed in a buffer containing b-glucuronidase/ sulfatase type H-5 from H. pomatia. The specificity of the hydrolysis was further investigated by addition of saccharolactone, an inhibitor of b-glucuronidase, but not sulfatase. This reaction was carried out in order to identify phase-1 metabolites that were conjugated with glucuronic acid/ sulfate (phase II) .

2. metabolites in urine collected 0 - 24 h post dose

3. metabolites in urine collected 0 - 4 h post dose

Mass balance studies were conducted in mice, rats and dogs following oral administration of rasagiline. In mice there was 79.4% recovery of the administered radioactivity in excreta (73.6% urine and 5.8% faeces) within 96 hours of a single oral dose (1 mg/kg) of 14C-rasagiline. In rats the amount of radioactivity excreted via the urine within 168 hours of a single oral dose (0.37 mg/kg) of 14C-rasagiline amounted to 89.4% of the administered dose with 5.8% of the dose recovered from faeces during the same time interval. The total recovery of radioactivity from excreta within 168 hours was therefore 95.2%. Dogs excreted approximately 83% of the administered radioactivity via urine within 144 hours of a single oral dose (1 mg/kg) of 14C-rasagiline. Excretion in faeces amounted to 5.3% whilst 4.8% was recovered from cage washings over the same time period. Thus the total recovery of radioactivity within 144 hours amounted to 93%. Systemic (plasma) exposure to PAI and AI was quantified during the course of the majority of the toxicology studies. These investigations showed that exposure was linear at doses higher than the pharmacological selectivity for inhibition of MOA-B and was maintained up to about 5 mg/kg/day. At the higher doses that were used to satisfy regulatory requirements for the design of toxicological investigations exposure to PAI and AI was characterized by non-linear kinetics. Although this possibly indicated saturation of the elimination processes for both PAI and AI accumulation was only evident at the highest dose (60 mg/kg/day) used for mice in the 13-week study and the highest dose (21 mg/kg/day) used for the 52-week oral toxicity study in dogs. Surprisingly, and despite the rapid elimination half-life for PAI, repeated dosing sometimes resulted in greater exposure than seen after single doses. This is consistent with the irreversible binding of rasagiline to its target enzyme thus rendering enzyme turnover time an important determinant of kinetic behavior. This possibility is further substantiated by the reliance upon extra-hepatic and extra-renal clearance and the high volume of distribution already discussed. It is also likely that the binding to abundant intestinal MAO sites contributes to the high first pass effect. Thus it is conceivable that rasagiline specifically binds to specific tissue sites (probably MAO) until the available binding sites are saturated. Once the saturation threshold has been reached then the excess unbound drug will appear in plasma.

TOXICOLOGY

Acute Toxicity Studies

At the outset of the program the hydrochloride salt was selected as the development candidate. Subsequently the mesylate salt (designated TVP-1012) was chosen because of its superior stability profile. Bridging studies confirmed the similarity of the pharmacokinetic and toxicological profiles of the two salts. There was therefore no necessity to repeat the toxicology studies with the hydrochloride salt that were completed prior to the switch. Single dose toxicity studies were conducted by the intravenous route in rats and by the oral route in mice, rats and dogs. Studies were initially conducted with the hydrochloride salt and subsequently with the more stable mesylate salt. Mortalities were induced in rats by intravenous doses

>=69 mg/kg/day. Mortalities were induced in mice at oral doses of >=206 mg/kg, in rats at oral doses

>=155 mg/kg and in dogs at oral doses of >=84 mg/kg. Death was a result of the functional neuropharmacological changes that can be anticipated when excessive doses of a molecule capable of inhibiting the oxidation of biogenic amines is administered. The maximal non-lethal oral dose for rats and mice was about 100 mg/kg/day and the maximum tolerable dose (MTD) in dogs was 42 mg/kg. These doses represent considerable multiples of the recommended clinically relevant maximum dose of 1 mg/patient/day.

Long-Term Toxicity Studies

The rat and dog were selected for the conduct of repeat dose toxicity studies, both species having been shown to be pharmacologically responsive to rasagiline-induced inhibition of MAO-B. Repeat dose intravenous toxicity studies of 4-weeks duration were conducted at maximum doses of 3 mg/kg/day in rats and 5 mg/kg/day in dogs. Repeat dose oral toxicity studies of up to 26 weeks duration were conducted in rats employing doses spanning the range 0.14 to 17 mg/kg/day and of up to 52 weeks duration in dogs employing doses spanning 0.28 to 21.0 mg/kg/day. The multiples of the systemic exposures to PAI and AI across the range of doses used for the repeat dose toxicity studies in rats and dogs are compared with the clinically relevant human exposure at the maximum recommended daily dose of 1 mg/day/patient in the following Table.

Table 9.

Comparison of the Achieved Systemic Exposures to PAI and AI Over the Range of Doses used for Repeat Dose Oral Toxicity Studies in Rats and Dogs with Human Clinical Exposure at 1 mg/Patient/Day.

*

Human exposure data taken from clinical study TVP-1012/231: Tolerability of TVP-1012, a Novel MAO-B Inhibitor, in Parkinson's disease patients.

Thus the lowest doses used for the repeat dose toxicity studies afforded at least a 2-fold multiple of the mean Cmax and AUClast values for PAI in humans receiving 1 mg/day. By contrast, the highest doses used for the repeat dose toxicology studies afforded at least a 250-fold multiple of Cmax and AUClast values for PAI in humans receiving 1 mg/day. After intravenous and oral dosing the principal manifestations of toxicity were related to the loss of selectivity for MAO-B (i.e. reduced food intake and weight gain and hyperactivity and/or aggression in rats). At the higher oral doses these findings were sometimes accompanied by increases in liver weight and adaptive changes in hepatocyte morphology in rats. The liver changes were consistent with changes observed in rats treated with hepatic microsomal enzyme inducers, there was however no evidence from studies that measured hepatic microsomal proteins to support this hypothesis. Suspected changes in thyroid and bladder morphology identified in the rat 13-week oral study were not corroborated by findings in either the 4-week or 26-week rat oral studies. The no adverse effect levels (NOAELS) defined after 26 weeks' treatment of rats and 52 weeks' treatment of dogs were

mg/kg/day (for both rats and dogs). In terms of AUClast values, the animal NOAELs afford multiples of at least 15-fold with respect to exposure to PAI at the clinical dose of 1 mg/patient/day.Studies were also conducted to examine whether co-administration of rasagiline with levodopa and a peripheral decarboxylase inhibitor (carbidopa) can produce effects other than the expected dopaminergic actions. There were no effects in rats or dogs given rasagiline/carbidopa/levodopa that could not be attributed to amplification of the effects of levodopa/carbidopa.Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis: Two year carcinogenicity studies were conducted in CD-1 mice at oral (gavage) doses of 1, 15, and 45 mg/kg and in Sprague-Dawley rats at oral (gavage) doses of 0.3, 1, and 3 mg/kg (males) or 0.5, 2, 5, and 17 mg/kg (females). In rats, there was no increase in tumors at any dose tested. Plasma exposures at the highest dose tested were approximately 33 and 260 times, in male and female rats, respectively, the expected plasma exposures in humans at the maximum recommended dose (MRD) of 1 mg/day.In mice, there was an increase in lung tumors (combined adenomas/carcinomas) at 15 and 45 mg/kg males and females. Plasma exposures associated with the no-effect dose (1 mg/kg) were approximately 5 times those expected in humans at the MRD.The carcinogenic potential of rasagiline administered in combination with levodopa/carbidopa has not been examined.Mutagenesis: Rasagiline was reproducibly clastogenic in in vitro chromosomal aberration assays in human lymphocytes in the presence of metabolic activation and was mutagenic and clastogenic in the in vitro mouse lymphoma TK assay in the absence and presence of metabolic activation. Rasagiline was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vivo unscheduled DNA synthesis assay, and the in vivo micronucleus assay in CD-1 mice. Rasagiline was also negative in the in vivo micronucleus assay in CD-1 mice when administered in combination with levodopa/carbidopa.Impairment of Fertility: Rasagiline had no effect on mating performance or fertility in male rats treated prior to and throughout the mating period, or in female rats treated from prior to mating through day 17 of gestation at oral doses up to 3 mg/kg/day (approximately 30 times the expectedplasma rasagiline exposure (AUC) at the maximum recommended human dose [1 mg/day]). The effect of rasagiline administered in combination with levodopa/carbidopa on mating and fertility has not been examined.Reproductive Toxicity StudiesNo effect on embryo-fetal development was observed in a combined mating/fertility and embryo- fetal development study in female rats at doses up to 3 mg/kg/day (approximately 30 times the expected plasma rasagiline exposure (AUC) at the maximum recommended human dose [MRHD, 1 mg/day]). Effects on embryo-fetal development in rabbit have not been adequately assessed.In a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) orally, from the beginning of organogenesis to day 20 post-partum, offspring survival was decreased and offspring body weight was reduced at doses of 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the expected plasma rasagiline exposure [AUC] at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is 1 times the MRHD on a mg/m2 basis. Rasagiline's effect on physical and behavioral development was not adequately assessed in this study.Rasagiline may be given as an adjunct therapy to levodopa/carbidopa treatment. In a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) throughout the period of organogenesis, there was an increased incidence of wavy ribs in fetuses from rats treated with rasagiline in combination withlevodopa/carbidopa at 1/80/20 mg/kg/day (approximately 8 times the plasma AUC expected in humans at the MRHD and 1/1 times the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m2 basis). In a study in which pregnant rabbits were dosed throughout the period of organogenesis with rasagiline alone (3 mg/kg) or in combination with levodopa/carbidopa (rasagiline: 0.1, 0.6, 1.2 mg/kg, levodopa/carbidopa: 80/20 mg/kg/day), an increase in embryo-fetal death was noted at rasagiline doses of 0.6 and 1.2 mg/kg/day when administered in combination with levodopa/carbidopa (approximately 7 and 13 times, respectively, the plasma rasagiline AUC at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (1/1 times the MRHD on a mg/m2 basis) and to a greater extent when rasagiline (at all doses; 1-13 times the plasma rasagiline AUC at the MRHD) was administered in combination with levodopa/carbidopa.BIBLIOGRAPHYPreclinicalFinberg JPM, Lamensdorf I, Commissiong JW, Youdim MBH. Pharmacology and neuroprotective properties of rasagiline. J Neural Transm 1996; [Suppl] 48:95-101.Finberg JPM and Youdim MBH. Pharmacological properties of the anti-parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviors. Neuropharmacology 2002; 43:1110-1118.Gotz ME, Breithaupt W, Sautter J, Kupsch A, Schwarz J, Oertel WH, Youdim MBH, Riederer P, Gerlach. Chronic TVP-1012 (rasagiline) dose - activity response of monoamine oxidases A and B in the brain of the common marmoset. J Neural Transm 1998; [Suppl] 52:271-278.Kupsch A, Sautter J, Gotz ME, Breithaupt W, Schwarz J, Youdim MBH, Riederer P, Gerlach M, Oertel WH. Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline. J Neural Transm 2001; 108:985-1009.Lamensdorf I, Youdim MBH, Finberg JPM. Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo. J Neurochem 1996; 67:1532-1539.Speiser Z, Levy R, Cohen S. Effects of N-propargyl-1-(R)aminoindan (rasagiline) in models of motor and cognition disorders. J Neural Transm 1998; [Suppl] 52:287-300.Speiser Z, Katzir O, Rehavi M, Zabarski T, Cohen S. Sparing by rasagiline (TVP-1012) of cholinergic functions and behavior in the postnatal anoxia rat. Pharmacol Biochem Behav 1998; 60:387-393.Youdim MBH, Gross A, Finberg JPM. Rasagiline [N-propargyl-1R (+)-aminoindan], a selective and potent inhibitor of mitocholdrial monoamine oxidase B. Br J Pharmaco 2001; 132(2)500-506.Youdim MB, Wadia A, Tatton W, Weinstock M. The anti-Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo. Ann N Y Acad Sci 2001; 939:450-458.Finberg JPM, Takeshima T, Johnston JM, Commissiong JW. Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B inhibitor. (Neuropharmacology and Neurotoxicology) Neuroreport 1998; 9:703-707Huang W, Chen Y, Shohami E, Weinstock M. Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse. European J Pharmacology 1999; 366:127-135.Abu-Raya S, Blaugrund E, Trembovler V, Shilderman-Bloch E, Shohami E, LazaroviciP. Rasagiline, a monoamine oxidase-B inhibitor, protects NGF-differentiated PC12 cells against oxygen-glucose deprivation. J Neuroscience Research 1999; 58:456-463.Speiser Z, Mayk A, Eliash S, Cohen S. Studies with rasagiline, a MAO-B inhibitor, in experimental focal ischemia in the rat. J Neural Transm 1999; 106:593-606.Abu-Raya S, Blaugrund E, Trembovler V, Lazarovici P. Rasagiline, a novel monoamine oxidase-B inhibitor with neuroprotective effects under ischemic conditions in PC-12 cells. Drug Devel Res 2000; 50:285-290.Carrillo MC, Minami C, Kitani K, Maruyama W, Ohashi K, Yamamoto T, Naoi M, Kanai S, Youdim MBH. Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat. Life Sci 2000; 67(5):577-585.Goggi J, Theofilopoulos S, Riaz SS, Jauniaux E, Stern GM, Bradford HF. The neuronal survival effects of rasagiline and deprenyl on fetal human and rat ventral mesencephalic neurones in culture. (Neuropharmacology and Neurotoxicology) Neuroreport 2000; 11(18):3937-3941.Eliash S, Speiser Z, Cohen S. Rasagiline and its (S) enantiomer increase survival and prevent stroke in salt-loaded stroke-prone spontaneously hypertensive rats. J Neural Transm 2001; 108:909-923.Akao Y., Maruyama W., Shamoto-Nagai M.S., Youdim M.B.H., Naoi M. An anti- Parkinson's disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic Bcl-2 in human dopaminergic SH-SY5Y cells. Neurosci Lett. 2002; 326(2):105-108.Naoi M, Maruyama W, Akao Y, Yi H. Mitochondria determine the survival and death in apoptosis by an endogenous neurotoxin, N-methyl(R)salsolinol, and neuroprotection by propargylamines. J Neural Transm 2002 May; 109(5-6):607-621.Abu-Raya S, Tabakman R, Blaugrund E, Trembovler V, Lazarovici P. Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells. Eur J Pharmacol 2002; 434(3):109-116.Maruyama W, Takahashi T., Youdim MBH, Naoi M. The anti-parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells. J Neural Transm 2002; 109:467-481.Maruyama W, Akao Y, Youdim MB, Davis BA, Naoi M. Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J Neurochem 2001; 78:727-735.ClinicalStudy TVP-1012/232 (TEMPO) A Multicenter Double-Blind, Placebo-Controlled, Parallel Group, Phase III Clinical Study for the Efficacy, Tolerability and Safety of Two Doses of Rasagiline Mesylate in Early Parkinson's Disease (PD) Patients Not Treated with Levodopa - Arch Neurol. 2002; 59:1937-1943Study TVP-1012/133 (PRESTO) A Multicenter, US and Canada, Double Blind, Randomized, Placebo-Controlled, Parallel Group Study, for the Efficacy, Tolerability and Safety of Rasagiline Mesylate in Levodopa Treated Parkinson's Disease Patients with Motor Fluctuations - Arch Neurol. 2005; 62:241-248Study TVP-1012/122 (LARGO) A Multicenter, Double-Blind, Double-Dummy, Randomized, Placebo and Entacapone-Controlled, Parallel Group Study for the Efficacy, Tolerability and Safety of Rasagiline Mesylate in Levodopa Treated Parkinson's Disease Patients with Motor Fluctuations - Lancet 2005; 365:947-54Study TVP-1012/233 (TEMPO-Extension) A Multicenter, Open-Label, Phase III Study for the Safety, Tolerability and Clinical Effect of Rasagiline Mesylate in Patients with Parkinson's Disease - Arch Neurol. 2004; 61:561-566

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

: Two year carcinogenicity studies were conducted in CD-1 mice at oral (gavage) doses of 1, 15, and 45 mg/kg and in Sprague-Dawley rats at oral (gavage) doses of 0.3, 1, and 3 mg/kg (males) or 0.5, 2, 5, and 17 mg/kg (females). In rats, there was no increase in tumors at any dose tested. Plasma exposures at the highest dose tested were approximately 33 and 260 times, in male and female rats, respectively, the expected plasma exposures in humans at the maximum recommended dose (MRD) of 1 mg/day.

In mice, there was an increase in lung tumors (combined adenomas/carcinomas) at 15 and 45 mg/kg males and females. Plasma exposures associated with the no-effect dose (1 mg/kg) were approximately 5 times those expected in humans at the MRD. The carcinogenic potential of rasagiline administered in combination with levodopa/carbidopa has not been examined.

Mutagenesis: Rasagiline was reproducibly clastogenic in in vitro chromosomal aberration assays in human lymphocytes in the presence of metabolic activation and was mutagenic and clastogenic in the in vitro mouse lymphoma TK assay in the absence and presence of metabolic activation. Rasagiline was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vivo unscheduled DNA synthesis assay, and the in vivo micronucleus assay in CD-1 mice. Rasagiline was also negative in the in vivo micronucleus assay in CD-1 mice when administered in combination with levodopa/carbidopa.

Impairment of Fertility

: Rasagiline had no effect on mating performance or fertility in male rats treated prior to and throughout the mating period, or in female rats treated from prior to mating through day 17 of gestation at oral doses up to 3 mg/kg/day (approximately 30 times the expected

plasma rasagiline exposure (AUC) at the maximum recommended human dose [1 mg/day]). The effect of rasagiline administered in combination with levodopa/carbidopa on mating and fertility has not been examined.

Reproductive Toxicity Studies

No effect on embryo-fetal development was observed in a combined mating/fertility and embryo- fetal development study in female rats at doses up to 3 mg/kg/day (approximately 30 times the expected plasma rasagiline exposure (AUC) at the maximum recommended human dose [MRHD, 1 mg/day]). Effects on embryo-fetal development in rabbit have not been adequately assessed. In a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) orally, from the beginning of organogenesis to day 20 post-partum, offspring survival was decreased and offspring body weight was reduced at doses of 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the expected plasma rasagiline exposure [AUC] at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is 1 times the MRHD on a mg/m2 basis. Rasagiline's effect on physical and behavioral development was not adequately assessed in this study. Rasagiline may be given as an adjunct therapy to levodopa/carbidopa treatment. In a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) throughout the period of organogenesis, there was an increased incidence of wavy ribs in fetuses from rats treated with rasagiline in combination with levodopa/carbidopa at 1/80/20 mg/kg/day (approximately 8 times the plasma AUC expected in humans at the MRHD and 1/1 times the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m2 basis). In a study in which pregnant rabbits were dosed throughout the period of organogenesis with rasagiline alone (3 mg/kg) or in combination with levodopa/carbidopa (rasagiline: 0.1, 0.6, 1.2 mg/kg, levodopa/carbidopa: 80/20 mg/kg/day), an increase in embryo-fetal death was noted at rasagiline doses of 0.6 and 1.2 mg/kg/day when administered in combination with levodopa/carbidopa (approximately 7 and 13 times, respectively, the plasma rasagiline AUC at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (1/1 times the MRHD on a mg/m2 basis) and to a greater extent when rasagiline (at all doses; 1-13 times the plasma rasagiline AUC at the MRHD) was administered in combination with levodopa/carbidopa.

BIBLIOGRAPHY

Preclinical

1. Finberg JPM, Lamensdorf I, Commissiong JW, Youdim MBH. Pharmacology and neuroprotective properties of rasagiline. J Neural Transm 1996; [Suppl] 48:95-101.

2. Finberg JPM and Youdim MBH. Pharmacological properties of the anti-parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviors. Neuropharmacology 2002; 43:1110-1118.

3. Gotz ME, Breithaupt W, Sautter J, Kupsch A, Schwarz J, Oertel WH, Youdim MBH, Riederer P, Gerlach. Chronic TVP-1012 (rasagiline) dose - activity response of monoamine oxidases A and B in the brain of the common marmoset. J Neural Transm 1998; [Suppl] 52:271-278.

4. Kupsch A, Sautter J, Gotz ME, Breithaupt W, Schwarz J, Youdim MBH, Riederer P, Gerlach M, Oertel WH. Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline. J Neural Transm 2001; 108:985-1009.

5. Lamensdorf I, Youdim MBH, Finberg JPM. Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo. J Neurochem 1996; 67:1532-1539.

6. Speiser Z, Levy R, Cohen S. Effects of N-propargyl-1-(R)aminoindan (rasagiline) in models of motor and cognition disorders. J Neural Transm 1998; [Suppl] 52:287-300.

7. Speiser Z, Katzir O, Rehavi M, Zabarski T, Cohen S. Sparing by rasagiline (TVP-1012) of cholinergic functions and behavior in the postnatal anoxia rat. Pharmacol Biochem Behav 1998; 60:387-393.

8. Youdim MBH, Gross A, Finberg JPM. Rasagiline [N-propargyl-1R (+)-aminoindan], a selective and potent inhibitor of mitocholdrial monoamine oxidase B. Br J Pharmaco 2001; 132(2)500-506.

9. Youdim MB, Wadia A, Tatton W, Weinstock M. The anti-Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo. Ann N Y Acad Sci 2001; 939:450-458.

10. Finberg JPM, Takeshima T, Johnston JM, Commissiong JW. Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B inhibitor. (Neuropharmacology and Neurotoxicology) Neuroreport 1998; 9:703-707

11. Huang W, Chen Y, Shohami E, Weinstock M. Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse. European J Pharmacology 1999; 366:127-135.

12. Abu-Raya S, Blaugrund E, Trembovler V, Shilderman-Bloch E, Shohami E, Lazarovici P. Rasagiline, a monoamine oxidase-B inhibitor, protects NGF-differentiated PC12 cells against oxygen-glucose deprivation. J Neuroscience Research 1999; 58:456-463.

13. Speiser Z, Mayk A, Eliash S, Cohen S. Studies with rasagiline, a MAO-B inhibitor, in experimental focal ischemia in the rat. J Neural Transm 1999; 106:593-606.

14. Abu-Raya S, Blaugrund E, Trembovler V, Lazarovici P. Rasagiline, a novel monoamine oxidase-B inhibitor with neuroprotective effects under ischemic conditions in PC-12 cells. Drug Devel Res 2000; 50:285-290.

15. Carrillo MC, Minami C, Kitani K, Maruyama W, Ohashi K, Yamamoto T, Naoi M, Kanai S, Youdim MBH. Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat. Life Sci 2000; 67(5):577-585.

16. Goggi J, Theofilopoulos S, Riaz SS, Jauniaux E, Stern GM, Bradford HF. The neuronal survival effects of rasagiline and deprenyl on fetal human and rat ventral mesencephalic neurones in culture. (Neuropharmacology and Neurotoxicology) Neuroreport 2000; 11(18):3937-3941.

17. Eliash S, Speiser Z, Cohen S. Rasagiline and its (S) enantiomer increase survival and prevent stroke in salt-loaded stroke-prone spontaneously hypertensive rats. J Neural Transm 2001; 108:909-923.

18. Akao Y., Maruyama W., Shamoto-Nagai M.S., Youdim M.B.H., Naoi M. An anti- Parkinson's disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic Bcl-2 in human dopaminergic SH-SY5Y cells. Neurosci Lett. 2002; 326(2):105-108.

19. Naoi M, Maruyama W, Akao Y, Yi H. Mitochondria determine the survival and death in apoptosis by an endogenous neurotoxin, N-methyl(R)salsolinol, and neuroprotection by propargylamines. J Neural Transm 2002 May; 109(5-6):607-621.

20. Abu-Raya S, Tabakman R, Blaugrund E, Trembovler V, Lazarovici P. Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells. Eur J Pharmacol 2002; 434(3):109-116.

21. Maruyama W, Takahashi T., Youdim MBH, Naoi M. The anti-parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells. J Neural Transm 2002; 109:467-481.

22. Maruyama W, Akao Y, Youdim MB, Davis BA, Naoi M. Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J Neurochem 2001; 78:727-735. Clinical

23. Study TVP-1012/232 (TEMPO) A Multicenter Double-Blind, Placebo-Controlled, Parallel Group, Phase III Clinical Study for the Efficacy, Tolerability and Safety of Two Doses of Rasagiline Mesylate in Early Parkinson's Disease (PD) Patients Not Treated with Levodopa - Arch Neurol. 2002; 59:1937-1943

24. Study TVP-1012/133 (PRESTO) A Multicenter, US and Canada, Double Blind, Randomized, Placebo-Controlled, Parallel Group Study, for the Efficacy, Tolerability and Safety of Rasagiline Mesylate in Levodopa Treated Parkinson's Disease Patients with Motor Fluctuations - Arch Neurol. 2005; 62:241-248

25. Study TVP-1012/122 (LARGO) A Multicenter, Double-Blind, Double-Dummy, Randomized, Placebo and Entacapone-Controlled, Parallel Group Study for the Efficacy, Tolerability and Safety of Rasagiline Mesylate in Levodopa Treated Parkinson's Disease Patients with Motor Fluctuations - Lancet 2005; 365:947-54

26. Study TVP-1012/233 (TEMPO-Extension) A Multicenter, Open-Label, Phase III Study for the Safety, Tolerability and Clinical Effect of Rasagiline Mesylate in Patients with Parkinson's Disease - Arch Neurol. 2004; 61:561-566

Clinical