Azilect (Rasagiline mesylate) (rasagiline tablets) is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa.

The effectiveness of Azilect (Rasagiline mesylate) was demonstrated in patients with early Parkinson's disease who were receiving Azilect (Rasagiline mesylate) as monotherapy and who were not receiving any concomitant dopaminergic therapy. The effectiveness of Azilect (Rasagiline mesylate) as adjunct therapy was demonstrated in patients with Parkinson's disease who were treated with levodopa.

Azilect (Rasagiline mesylate) 0.5 mg Tablets: White to off-white, round, flat, beveled tablets, debossed with "GIL 0.5" on one side and plain on the other side containing, as the active ingredient, rasagiline mesylate equivalent to 0.5 mg of rasagiline base.

Azilect (Rasagiline mesylate) 1 mg Tablets: White to off-white, round, flat, beveled tablets, debossed with "GIL 1" on one side and plain on the other side containing, as the active ingredient, rasagiline mesylate equivalent to 1 mg of rasagiline base.

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Severe CNS toxicity associated with hyperpyrexia has been reported with the combined treatment of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a non-selective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl) and rasagiline (Azilect (Rasagiline mesylate) ). These adverse reactions are often described as "serotonin syndrome" which can result in death. In the post-marketing period, non-fatal cases of serotonin syndrome have been reported in patients treated with antidepressants concomitantly with Azilect (Rasagiline mesylate) .

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).

Azilect (Rasagiline mesylate) clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with Azilect (Rasagiline mesylate) , but the following antidepressants and doses were allowed in the Azilect (Rasagiline mesylate) trials: amitriptyline ≤ 50 mg/daily, trazodone ≤ 100 mg/daily, citalopram ≤ 20 mg/daily, sertraline ≤ 100 mg/daily and paroxetine ≤ 30 mg/daily.

Although a small number of rasagiline-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. Furthermore, because the mechanisms of these reactions are not fully understood, it seems prudent, in general, to avoid the combination of Azilect (Rasagiline mesylate) with any antidepressant. At least 14 days should elapse between discontinuation of Azilect (Rasagiline mesylate) 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 Azilect (Rasagiline mesylate) [see ].

Azilect (Rasagiline mesylate) is a selective inhibitor of monoamine oxidase (MAO)-B at the recommended doses of 0.5 or 1 mg daily. Azilect (Rasagiline mesylate) should not be used at daily doses exceeding 1 mg/day (or 0.5 mg/day for patients with mild hepatic impairment or in patients using concomitant ciprofloxacin or another CYP1A2 inhibitor) because of the risks of hypertensive crisis and other adverse reactions associated with nonselective inhibition of MAO .

Dietary tyramine restriction is not ordinarily required with ingestion of most foods and beverages that may contain tyramine, during treatment with recommended doses of Azilect (Rasagiline mesylate) . However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts (i.e., > 150 mg) of tyramine and could potentially cause a hypertensive "cheese" reaction in patients taking Azilect (Rasagiline mesylate) even at the recommended doses due to mild increased sensitivity to tyramine. Patients should be advised to avoid foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of Azilect (Rasagiline mesylate) because of the potential for large increases in blood pressure. 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 treatment, in which most patients did not follow dietary tyramine restriction.

Rare cases of hypertensive crisis have been reported in the post-marketing period in patients after ingesting unknown amounts of tyramine-rich foods while taking recommended doses of Azilect (Rasagiline mesylate) .

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. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

In placebo controlled studies of Azilect (Rasagiline mesylate) given in combination with levodopa, the incidence of postural hypotension consisting of a systolic blood pressure decrease ( 30 mm Hg) or a diastolic blood pressure decrease ( 20 mm Hg) after standing was 13.4 % with Azilect (Rasagiline mesylate) (1 mg/day) compared to 8.5 % with placebo.

At the 1 mg dose, the frequency of orthostatic hypotension at any time during the study was approximately 44 % for Azilect (Rasagiline mesylate) vs 33% for placebo for mild to moderate systolic blood pressure decrements ( 20 mm Hg), 40 % for Azilect (Rasagiline mesylate) vs 33 % for placebo for mild to moderate diastolic blood pressure decrements ( 10 mm Hg), 7 % for Azilect (Rasagiline mesylate) vs 3 % for placebo for severe systolic blood pressure decrements ( 40 mm Hg), and 9 % for Azilect (Rasagiline mesylate) 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 postural hypotension for both systolic and diastolic blood pressure.

Clinical trial data further suggest that postural hypotension occurs most frequently in the first two months of Azilect (Rasagiline mesylate) treatment and tends to decrease over time.

Some patients treated with Azilect (Rasagiline mesylate) 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 30 or diastolic > 20 mm Hg) was higher for Azilect (Rasagiline mesylate) 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 Azilect (Rasagiline mesylate) 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 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.

In studies in which Azilect (Rasagiline mesylate) (1 mg/day) was given in conjunction with levodopa, Azilect (Rasagiline mesylate) produced an increased incidence of a significant, high blood pressure (e.g., systolic > 180 or diastolic > 100 mm Hg) of 4% compared to 3% for placebo.

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 Azilect (Rasagiline mesylate) (2 %) compared to placebo (1 %).

There was no increased frequency of the incidence of hypertension as an adverse reaction in the adjunctive treatment pivotal trials for Azilect (Rasagiline mesylate) treatment vs placebo.

There was no observed increased risk for increasing blood pressure or high blood pressure (based upon various measurements and analyses) or for the development of hypertension as an adverse reaction in the monotherapy study for 1 mg daily Azilect (Rasagiline mesylate) treatment (vs placebo).

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 reaction in approximately 5% of patients treated with 0.5 mg/day Azilect (Rasagiline mesylate) , 4% of patients treated with 1 mg/day Azilect (Rasagiline mesylate) 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 rasagiline and none of the placebo-treated patients.

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

Patients with a major psychotic disorder should ordinarily not be treated with Azilect (Rasagiline mesylate) because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, many treatments for psychosis that decrease in central dopaminergic tone may decrease the effectiveness of Azilect (Rasagiline mesylate) .

Azilect (Rasagiline mesylate) administration may cause or exacerbate psychotic-like behavior based upon post-marketing reports. This adverse reaction has been reported with many anti-Parkinsonian drugs that increase central dopaminergic tone. This abnormal behavior has been exhibited by one or more of a variety of manifestations including paranoia, confusional state/confusion, psychotic disorder, agitation, delusion, and hallucinations.

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. .

Withdrawal emergent hyperpyrexia was not reported in the Azilect (Rasagiline mesylate) clinical development program.

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During the clinical development of Azilect (Rasagiline mesylate) , 1361 Parkinson's disease patients received rasagiline as initial monotherapy or as adjunct therapy to levodopa. As these two populations differ, not only in the adjunct use of levodopa during rasagiline treatment, but also in the severity and duration of their disease, they may have differential risks for various adverse reactions. Therefore, most of the adverse reactions data in this section are presented separately for each population.

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 rates in the clinical trials of another drug and may not reflect the rates of adverse reactions observed in practice.

Patients Receiving Azilect (Rasagiline mesylate) as Initial Monotherapy Treatment

Adverse Reactions Leading to Discontinuation in Controlled Clinical Studies
In the double-blind, placebo-controlled trials conducted in patients receiving Azilect (Rasagiline mesylate) as monotherapy, approximately 5% of the 149 patients treated with rasagiline discontinued treatment due to adverse reactions compared to 2% of the 151 patients who received placebo.

The only adverse reaction that led to the discontinuation of more than one patient was hallucinations.

Adverse Reaction Incidence in Controlled Clinical Studies
The most commonly observed adverse reactions were those in which the treatment difference for the incidence in Azilect (Rasagiline mesylate) -treated patients was ≥ 3 % greater than the incidence in the placebo-treated patients and included flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists treatment-emergent adverse reactions that occurred in ≥ 2% of patients receiving Azilect (Rasagiline mesylate) as monotherapy participating in the double-blind, placebo-controlled trial and were numerically more frequent than in the placebo group.

Other events of potential clinical importance reported by 1% or more of patients receiving Azilect (Rasagiline mesylate) as monotherapy, and at least as frequent as in the placebo group, in descending order of frequency include: dizziness, diarrhea, chest pain, albuminuria, allergic reaction, alopecia, angina pectoris, anorexia, asthma, hallucinations, impotence, leukopenia, libido decreased, liver function tests abnormal, skin carcinoma, syncope, vesiculobullous rash, vomiting.

There were no significant differences in the safety profile based on age or gender.

Patients Receiving Azilect (Rasagiline mesylate) as Adjunct to Levodopa Therapy

Adverse Reactions Leading to Discontinuation in Controlled Clinical Studies
In a double-blind, placebo-controlled trial (Study 1) conducted in patients treated with Azilect (Rasagiline mesylate) as adjunct to levodopa therapy, approximately 9% of the 164 patients treated with Azilect (Rasagiline mesylate) 0.5 mg/day and 7% of the 149 patients treated with Azilect (Rasagiline mesylate) 1 mg/day discontinued treatment due to adverse reactions compared to 6% of the 159 patients who received placebo. The adverse reactions that led to discontinuation of more than one rasagiline-treated patient were: diarrhea, weight loss, hallucination, and rash. Adverse event reporting was considered more reliable for Study 1 than for the second controlled trial (Study 2); therefore only the adverse event data from Study 1 are presented in this section of labeling.

Adverse Reactions: Incidence in Controlled Clinical Studies
The most commonly observed adverse reactions were those in which the treatment difference for the incidence in Azilect (Rasagiline mesylate) -treated patients (n=149) was ≥ 3 % greater than the incidence in the placebo-treated patients (n=159) and included dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, and fall.

Table 2 lists treatment-emergent adverse reactions that occurred in ≥ 2% of patients treated with Azilect (Rasagiline mesylate) 1 mg/day as adjunct to levodopa therapy participating in the double-blind, placebo-controlled trial (Study 1) and that were numerically more frequent than the placebo group. The table also shows the rates for the 0.5 mg group in Study 1.

Several of the more common adverse reactions seemed dose-related, including weight loss, postural hypotension, and dry mouth.

Other adverse reactions of potential clinical importance reported in Study 1 by 1% or more of patients treated with rasagiline 1 mg/day as adjunct to levodopa therapy, and at least as frequent as in the placebo group, in descending order of frequency include : skin carcinoma, anemia, albuminuria, amnesia, arthritis, bursitis, cerebrovascular accident, confusion, dysphagia, epistaxis, leg cramps, pruritus, skin ulcer.

There were no significant differences in the safety profile based on age or gender.

Other Adverse Reactions Observed During All Phase 2/3 Clinical Trials

Rasagiline was administered to approximately 1361 patients during all PD phase 2/3 clinical trials. About 283 patients received rasagiline for at least one year, approximately 410 patients received rasagiline for at least two years, 116 patients received rasagiline for at least 3 years, and 245 patients received rasagiline for more than 3 years, with some patients treated for more than 5 years. The long-term safety profile was similar to that observed with shorter duration exposure.

The frequencies listed below represent the proportion of the 1361 individuals exposed to rasagiline who experienced events of the type cited.

All events that occurred at least twice (or once for serious or potentially serious events), except those already listed above, trivial events, terms too vague to be meaningful, adverse events with no plausible relation to treatment, and events that would be expected in patients of the age studied, were reported without regard to determination of a causal relationship to rasagiline.

Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients, infrequent adverse events are defined as those occurring in at least 1/100 to 1/1000 patients and rare adverse events are defined as those occurring in fewer than 1/1000 patients.

Metabolic and Nutritional disorders: Infrequent:

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The concomitant use of Azilect (Rasagiline mesylate) 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 dose of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine). Elevated blood pressure was reported in another patient taking the recommended dose of Azilect (Rasagiline mesylate) and ophthalmic drops with a sympathomimetic medication (tetrahydrozoline).

Because Azilect (Rasagiline mesylate) is 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 Azilect (Rasagiline mesylate) with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies.

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MAO in the gastrointestinal tract and liver (primarily type A) is thought to provide vital protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a "hypertensive crisis," the so-called "cheese reaction". If large amounts of certain exogenous amines (e.g., from fermented cheese, herring, over-the-counter cough/cold medications) gain access to the systemic circulation because MAO-A has been inhibited, they cause release of norepinephrine which may result in a rise in systemic blood pressure. MAOIs that selectively inhibit MAO-B are largely devoid of the potential to cause tyramine-induced hypertensive crisis.

Results of a special tyramine challenge study indicate that rasagiline is selective for MAO-B at recommended doses and can ordinarily be used without dietary tyramine restriction. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts (i.e., > 150 mg) of tyramine and could potentially cause a hypertensive cheese reaction in patients taking Azilect (Rasagiline mesylate) due to mild increased sensitivity to tyramine. Patients should be advised to avoid foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of Azilect (Rasagiline mesylate) because of the potential for large increases in blood pressure. 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 treatment, in which most patients did not follow dietary tyramine restriction.

Despite the selective inhibition of MAO-B at recommended doses of Azilect (Rasagiline mesylate) , there have been post-marketing 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 Azilect (Rasagiline mesylate)

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Category C

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/m 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/m 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/m 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.

There are no adequate and well-controlled studies of rasagiline in pregnant women. Therefore, Azilect (Rasagiline mesylate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk secretion in females.

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 (Rasagiline mesylate) is administered to a nursing woman.

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No cases of Azilect (Rasagiline mesylate) 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 not observed with rasagiline during clinical development, may resemble those observed with non-selective MAO inhibitors (MAOIs).

Although no cases of overdose have been observed with rasagiline during the clinical development program, 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. For this reason, in cases of overdose with Azilect (Rasagiline mesylate) , dietary tyramine restriction should be observed for several weeks to avoid the risk of a hypertensive/cheese reaction.

A poison control center should be called for the most current treatment guidelines.

A post-marketing report described a single patient who developed a non-fatal serotonin syndrome after ingesting 100 mg of Azilect (Rasagiline mesylate) in a suicide attempt. Another patient who was treated in error with 4 mg Azilect (Rasagiline mesylate) daily and tramadol also developed a serotonin syndrome. One patient who was treated in error with 3 mg Azilect (Rasagiline mesylate) daily experienced alternating episodes of vascular fluctuations consisting of hypertension and orthostatic hypotension.

Azilect (Rasagiline mesylate) tablets contain rasagiline (as the mesylate), a propargylamine-based drug indicated for the treatment of idiopathic Parkinson's disease. It is designated chemically as: 1H-Inden-1-amine, 2, 3-dihydro-N-2-propynyl-, (1R)-, methanesulfonate. The empirical formula of rasagiline mesylate is (CHN)CHSO and its molecular weight is 267.34.

Its structural formula is:

Rasagiline mesylate is a white to off-white powder, freely soluble in water or ethanol and sparingly soluble in isopropanol. Each Azilect (Rasagiline mesylate) tablet for oral administration contains rasagiline mesylate equivalent to 0.5 mg or 1 mg of rasagiline base.

Each Azilect (Rasagiline mesylate) tablet also contains the following inactive ingredients: mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid and talc.

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Azilect (Rasagiline mesylate) functions as 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 Azilect (Rasagiline mesylate) 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 Azilect (Rasagiline mesylate) . 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 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.

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.

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.

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 (Rasagiline mesylate) can be administered with or without food .

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). experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP1A2 being the major isoenzyme involved in rasagiline metabolism. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway.

After oral administration of C-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 calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.

Special Populations

Hepatic Impairment
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 .

Renal Impairment
Following repeat dose administration (8 days) of rasagiline (1 mg/day) in subjects with moderate renal impairment, rasagiline exposure (AUC) was similar to rasagiline exposure in healthy subjects, while the major metabolite 1-AI exposure (AUC) was increased 1.5- fold in subjects with moderate renal impairment, compared to healthy subjects. Because 1-AI is not an MAO inhibitor, no dose adjustment is needed for patients with mild and moderate renal impairment. Data are not available for patients with severe renal impairment.

Elderly
Since age has little influence on rasagiline pharmacokinetics, it can be administered at the recommended dose in the elderly (≥ 65 years).

Pediatric
Azilect (Rasagiline mesylate) 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
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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 (Rasagiline mesylate)
Theophylline:
Effect of Azilect (Rasagiline mesylate) on Other Drugs
No additional trials have investigated the effect of Azilect (Rasagiline mesylate) on other drugs metabolized by the cytochrome P450 enzyme system. studies showed that rasagiline at a concentration of 1mcg/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.

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The effectiveness of Azilect (Rasagiline mesylate) for the treatment of Parkinson's disease was established in three 18- to 26-week, randomized, placebo-controlled trials. In one of these trials Azilect (Rasagiline mesylate) was given as initial monotherapy and in the other two as adjunctive therapy to levodopa.

The monotherapy trial 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 any anti-Parkinson's disease medication before receiving rasagiline treatment.

In this trial, 404 patients were randomly assigned to receive placebo (138 patients), rasagiline 1 mg/day (134 patients) or rasagiline 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).

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 3 displays the results of the monotherapy trial.

For the comparison between rasagiline 1 mg/day and placebo, no differences in effectiveness based on age or gender were detected.

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.). The first (Study 1) 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 (Study 2) was conducted outside of North America (several European countries, Argentina, Israel) and studied only a single dose (1 mg daily) of rasagiline 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, or "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 (Study 1) 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.

The first adjunct study (Study 1) 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), rasagiline 0.5 mg/day (164 patients), or rasagiline 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.

The second adjunct study (Study 2) 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), rasagiline 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 4 and 5). The lower dose (0.5 mg) of rasagiline also significantly reduced "OFF" time (Table 4), but had a numerically smaller effect than the 1 mg dose of rasagiline. In Study 2, the active comparator also reduced "OFF" time when compared to placebo.

In both studies, dosage reduction of levodopa was allowed within the first 6 weeks if dopaminergic side effects, including dyskinesia and hallucinations, emerged. In Study 1, 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 Study 2, 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 1 mg/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 performed during an "ON" period. In both scales, a negative response represents improvement. Tables 6 and 7 show these results for Studies 1 and 2.

Azilect (Rasagiline mesylate) 1 mg Tablets:

White to off-white, round, flat, beveled tablets, debossed with "GIL 1" on one side and plain on the other side.

Supplied as bottles of 30 tablets ( 54868-6206-0).

Storage:

Store at 25°C (77°F) with excursions permitted to 15°-30°C (59°-86°F).

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Patients should be advised not to exceed the maximum recommended daily dose of 1 mg/day (0.5 mg/day for subjects with mild hepatic impairment and subjects using concomitant ciprofloxacin and other CYP1A2 inhibitors).

The risk of using higher than recommended daily doses of Azilect (Rasagiline mesylate) should be explained, and a brief description of the hypertensive/cheese reaction provided.

The possibility exists that very tyramine-rich foods (e.g., aged cheese such as Stilton) could possibly cause an increase in blood pressure. Patients should be advised to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of Azilect (Rasagiline mesylate) because of the potential for large increases in blood pressure. If patients eat foods very rich in tyramine and do not feel well soon after eating, they should contact their healthcare provider .

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease (including Azilect (Rasagiline mesylate) ). Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges, or other urges while being treated with rasagiline. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges, or other intense urges while taking rasagiline. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking rasagiline.

Marketed by: TEVA Neuroscience, Inc., Kansas City, MO 64131Distributed by: TEVA Pharmaceuticals USA, Inc., North Wales, PA 19454Product of Israel

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