Azilect

Dosage Forms And Strengths

AZILECT 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 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.

Storage And Handling

AZILECT 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. Supplied as bottles of 30 tablets (NDC 68546-142-56).

AZILECT 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 (NDC 68546-229-56).

Storage

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

Marketed by: TEVA Neuroscience, Inc., Overland Park, KS 66211. Distributed by: TEVA Pharmaceuticals USA, Inc., North Wales, PA 19454. Revised: May 2014.

AZILECT (rasagiline tablets) is indicated for the treatment of Parkinson's disease (PD).

General Dosing Recommendations

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

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

The recommended doses of AZILECT should not be exceeded because of risk of hypertension.

Patients Taking Ciprofloxacin Or Other CYP1A2 Inhibitors

Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of AZILECT 0.5 mg once daily.

Patients With Hepatic Impairment

Patients with mild hepatic impairment should not exceed a dose of AZILECT 0.5 mg once daily. AZILECT should not be used in patients with moderate or severe hepatic impairment.

AZILECT is contraindicated for use with meperidine, tramadol, methadone, propoxyphene and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors, because of risk of serotonin syndrome. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with these medications.

AZILECT is contraindicated for use with St. John's wort and with cyclobenzaprine.

AZILECT is contraindicated for use with dextromethorphan because of risk of episode of psychosis or bizarre behavior.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypertension

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

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

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

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

Serotonin Syndrome

Serotonin syndrome has been reported with concomitant use of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a nonselective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl) and rasagiline (AZILECT). Serotonin syndrome has also been reported with concomitant use of AZILECT with meperidine, tramadol, methadone, or propoxyphene. AZILECT is contraindicated for use with meperidine, tramadol, methadone, propoxyphene and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors.

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

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

AZILECT clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with AZILECT, and the potential drug interaction between AZILECT and antidepressants has not been studied systematically. Although a small number of AZILECT-treated patients were concomitantly exposed to antidepressants (tricyclics n=115; SSRIs n=141), the exposure, both in dose and number of subjects, was not adequate to rule out the possibility of an untoward reaction from combining these agents. At least 14 days should elapse between discontinuation of AZILECT 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.

Falling Asleep During Activities Of Daily Living And Somnolence

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

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

In Study 3, somnolence was a common occurrence in patients receiving AZILECT and was more frequent in patients with Parkinson's disease receiving AZILECT than in respective patients receiving placebo (6% AZILECT compared to 4% Placebo).

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

Ciprofloxacin Or Other CYP1A2 Inhibitors

Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of AZILECT 0.5 mg once daily.

Hepatic Impairment

Rasagiline plasma concentration may increase in patients with hepatic impairment. Patients with mild hepatic impairment should be given the dose of AZILECT 0.5 mg once daily. AZILECT should not be used in patients with moderate or severe hepatic impairment.

Hypotension / Orthostatic Hypotension

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

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

In Study 2 where AZILECT was given as an adjunct therapy in patients not taking concomitant levodopa, there were 5 reports of orthostatic hypotension in patients taking AZILECT 1 mg (3.1%) and 1 report in patients taking placebo (0.6%).

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

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

The risk for post-treatment hypotension (e.g., systolic < 90 or diastolic < 50 mm Hg) combined with a significant decrease from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for AZILECT 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 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 AZILECT 0.5 mg, 9% of patients treated with AZILECT 1 mg and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with AZILECT 1 mg/day, no patients treated with AZILECT 0.5 mg/day and no placebo-treated patients.

Dyskinesia

When used as an adjunct to levodopa, AZILECT may cause dyskinesia or potentiate dopaminergic side effects and exacerbate pre-existing dyskinesia. In Study 3, the incidence of dyskinesia was 18% for patients treated with 0.5 mg or 1 mg AZILECT as an adjunct to levodopa and 10% for patients treated with placebo as an adjunct to levodopa. Decreasing the dose of levodopa may mitigate this side effect.

Hallucinations / Psychotic-Like Behavior

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

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

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

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

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

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

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

Impulse Control / Compulsive Behaviors

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

Withdrawal-Emergent Hyperpyrexia And Confusion

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

Melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2to 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).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

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

In mice, there was an increase in lung tumors (combined adenomas/carcinomas) at 15 and 45 mg/kg in males and females. At the lowest dose tested, plasma AUCs were approximately 5 times those expected in humans at the MRHD.

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 and in the in vivo micronucleus assay in mice. Rasagiline was also negative in the in vivo micronucleus assay in mice when administered in combination with levodopa/carbidopa.

Impairment of Fertility

Rasagiline had no effect on mating performance or fertility in rats treated prior to and throughout the mating period and continuing in females through gestation day 17 at oral doses of up to 3 mg/kg/day (approximately 30 times the plasma AUC in humans at the MRHD). The effect of rasagiline administered in combination with levodopa/carbidopa on mating and fertility has not been examined.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of rasagiline in pregnant women. AZILECT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a combined mating/fertility and embryo-fetal development study in pregnant rats, no effect on embryo-fetal development was observed at oral doses up to 3 mg/kg/day (approximately 30 times the plasma exposure (AUC) in humans at the maximum recommended human dose [MRHD, 1 mg/day]).

In pregnant rabbits administered rasagiline throughout the period of organogenesis at oral doses of up to 36 mg/kg/day, no developmental toxicity was observed. At the highest dose tested, the plasma AUC was approximately 800 times that in humans at the MRHD.

In pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) orally during gestation and lactation, offspring survival was decreased and offspring body weight was reduced at 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the plasma AUC in humans at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is similar to the MRHD on a mg/m² basis. The effect of rasagiline 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 pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) orally 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 rasagiline plasma AUC in humans at the MRHD and similar to the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m² basis). In pregnant rabbits dosed orally 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 rasagiline plasma AUC in humans at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (similar to the MRHD on a mg/m² basis) and to a greater extent when rasagiline (at all doses; 1-13 times the rasagiline plasma AUC in humans at the MRHD) was administered in combination with levodopa/carbidopa.

Nursing Mothers

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

It is not known whether this drug 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.

Pediatric Use

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

Geriatric Use

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

Hepatic Impairment

Rasagiline plasma concentration may be increased in patients with mild (up to 2 fold, Child-Pugh score 5-6), moderate (up to 7 fold, Child-Pugh score 7-9), and severe (Child-Pugh score 10-15) hepatic impairment. Patients with mild hepatic impairment should not exceed a dose of 0.5 mg/day. AZILECT should not be used in patients with moderate or severe hepatic impairment.

Renal Impairment

Dose adjustment of AZILECT is not required for patients with mild or moderate renal impairment because AZILECT plasma concentrations are not increased in patients with moderate renal impairment. Rasagiline has not been studied in patients with severe renal impairment.

SIDE EFFECTS

The following adverse reactions are described in more detail in the WARNINGS AND PRECAUTIONS section of the label:

• Hypertension
• Serotonin Syndrome
• Falling Asleep During Activities of Daily Living and Somnolence
• Hypotension / Orthostatic Hypotension
• Dyskinesia
• Hallucinations / Psychotic-Like Behavior
• Impulse Control /Compulsive Behaviors
• Withdrawal-Emergent Hyperpyrexia and Confusion
• Melanoma

Clinical Trials Experience

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

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

Monotherapy Use of AZILECT

In Study 1, approximately 5% of the 149 patients treated with AZILECT 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.

The most commonly observed adverse reactions in Study 1 (incidence in AZILECT-treated patients 3% or greater than the incidence in placebo-treated patients) included flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists adverse reactions that occurred in 2% or greater of patients receiving AZILECT as monotherapy and were numerically more frequent than in the placebo group in Study 1.

Table 1: Adverse Reactions* in Study 1

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

Adjunct Use of AZILECT

AZILECT was studied as an adjunct therapy without levodopa (Study 2), or as an adjunct therapy to levodopa, with some patients also taking dopamine agonists, COMT inhibitors, anticholinergics, or amantadine (Study 3 and Study 4).

In Study 2, approximately 8% of the 162 patients treated with AZILECT discontinued treatment due to adverse reactions compared to 4% of the 164 patients who received placebo.

Adverse reactions that led to the discontinuation of more than one patient were nausea and dizziness.

The most commonly observed adverse reactions in Study 2 (incidence in AZILECT-treated patients 3% or greater than incidence in placebo-treated patients) included peripheral edema, fall, arthralgia, cough, and insomnia. Table 2 lists adverse reactions that occurred in 2% or greater in patients receiving AZILECT as adjunct therapy without levodopa and numerically more frequent than in the placebo group in Study 2.

Table 2: Adverse Reactions* in Study 2

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

In Study 3, adverse event reporting was considered more reliable than Study 4; therefore, only the adverse event data from Study 3 are presented below.

In Study 3, approximately 9% of the 164 patients treated with AZILECT 0.5 mg/day and 7% of the 149 patients treated with AZILECT 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 AZILECT-treated patient were diarrhea, weight loss, hallucination, and rash.

The most commonly observed adverse reactions in Study 3 (incidence in AZILECT-treated patients 3% or greater than the incidence in placebo-treated patients) included dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, fall and tenosynovitis.

Table 3 lists adverse reactions that occurred in 2% or greater of patients treated with AZILECT 1 mg/day and that were numerically more frequent than the placebo group in Study 3.

Table 3: Adverse Reactions* in Study 3

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.

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 is contraindicated for use with AZILECT.

MAO Inhibitors

AZILECT is contraindicated for use with other MAO inhibitors because of the increased risk of nonselective MAO inhibition that may lead to a hypertensive crisis.

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 nonselective MAO inhibitors. Hypertensive crisis has been reported in patients taking the recommended dose of AZILECT and sympathomimetic medications. Severe hypertension has been reported in patients taking the recommended dose of AZILECT and ophthalmic drops containing sympathomimetic medications.

Because AZILECT 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 with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies.

Antidepressants

Concomitant use of AZILECT with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended. Concomitant use of AZILECT and MAO inhibitors is contraindicated.

Ciprofloxacin Or Other CYP1A2 Inhibitors

Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. This could result in increased adverse events. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of AZILECT 0.5 mg once daily.

Tyramine/Rasagiline Interaction

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

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

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

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

Dopaminergic Antagonists

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

Drug Abuse And Dependence

Controlled Substance

AZILECT is not a controlled substance.

Abuse

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

Dependence

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

Pregnancy Category C

There are no adequate and well-controlled studies of rasagiline in pregnant women. AZILECT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a combined mating/fertility and embryo-fetal development study in pregnant rats, no effect on embryo-fetal development was observed at oral doses up to 3 mg/kg/day (approximately 30 times the plasma exposure (AUC) in humans at the maximum recommended human dose [MRHD, 1 mg/day]).

In pregnant rabbits administered rasagiline throughout the period of organogenesis at oral doses of up to 36 mg/kg/day, no developmental toxicity was observed. At the highest dose tested, the plasma AUC was approximately 800 times that in humans at the MRHD.

In pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) orally during gestation and lactation, offspring survival was decreased and offspring body weight was reduced at 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the plasma AUC in humans at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is similar to the MRHD on a mg/m² basis. The effect of rasagiline 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 pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) orally 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 rasagiline plasma AUC in humans at the MRHD and similar to the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m² basis). In pregnant rabbits dosed orally 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 rasagiline plasma AUC in humans at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (similar to the MRHD on a mg/m² basis) and to a greater extent when rasagiline (at all doses; 1-13 times the rasagiline plasma AUC in humans at the MRHD) was administered in combination with levodopa/carbidopa.

The following adverse reactions are described in more detail in the WARNINGS AND PRECAUTIONS section of the label:

• Hypertension
• Serotonin Syndrome
• Falling Asleep During Activities of Daily Living and Somnolence
• Hypotension / Orthostatic Hypotension
• Dyskinesia
• Hallucinations / Psychotic-Like Behavior
• Impulse Control /Compulsive Behaviors
• Withdrawal-Emergent Hyperpyrexia and Confusion
• Melanoma

Clinical Trials Experience

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

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

Monotherapy Use of AZILECT

In Study 1, approximately 5% of the 149 patients treated with AZILECT 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.

The most commonly observed adverse reactions in Study 1 (incidence in AZILECT-treated patients 3% or greater than the incidence in placebo-treated patients) included flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists adverse reactions that occurred in 2% or greater of patients receiving AZILECT as monotherapy and were numerically more frequent than in the placebo group in Study 1.

Table 1: Adverse Reactions* in Study 1

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

Adjunct Use of AZILECT

AZILECT was studied as an adjunct therapy without levodopa (Study 2), or as an adjunct therapy to levodopa, with some patients also taking dopamine agonists, COMT inhibitors, anticholinergics, or amantadine (Study 3 and Study 4).

In Study 2, approximately 8% of the 162 patients treated with AZILECT discontinued treatment due to adverse reactions compared to 4% of the 164 patients who received placebo.

Adverse reactions that led to the discontinuation of more than one patient were nausea and dizziness.

The most commonly observed adverse reactions in Study 2 (incidence in AZILECT-treated patients 3% or greater than incidence in placebo-treated patients) included peripheral edema, fall, arthralgia, cough, and insomnia. Table 2 lists adverse reactions that occurred in 2% or greater in patients receiving AZILECT as adjunct therapy without levodopa and numerically more frequent than in the placebo group in Study 2.

Table 2: Adverse Reactions* in Study 2

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

In Study 3, adverse event reporting was considered more reliable than Study 4; therefore, only the adverse event data from Study 3 are presented below.

In Study 3, approximately 9% of the 164 patients treated with AZILECT 0.5 mg/day and 7% of the 149 patients treated with AZILECT 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 AZILECT-treated patient were diarrhea, weight loss, hallucination, and rash.

The most commonly observed adverse reactions in Study 3 (incidence in AZILECT-treated patients 3% or greater than the incidence in placebo-treated patients) included dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, fall and tenosynovitis.

Table 3 lists adverse reactions that occurred in 2% or greater of patients treated with AZILECT 1 mg/day and that were numerically more frequent than the placebo group in Study 3.

Table 3: Adverse Reactions* in Study 3

In a dose escalation study in patients on chronic levodopa therapy treated with 10 mg of AZILECT there were three reports of cardiovascular side effects (including hypertension and postural hypotension) which resolved following treatment discontinuation.

Although no cases of overdose have been observed with AZILECT during the clinical development program, the following description of presenting symptoms and clinical course is based upon overdose descriptions of nonselective MAO inhibitors.

The signs and symptoms of nonselective MAOI overdose may not appear immediately. Delays of up to 12 hours after ingestion of drug and the appearance of signs may occur. The peak intensity of the syndrome may not be reached until for a day following the overdose. Death has been reported following overdose; therefore, immediate hospitalization, with continuous patient observation and monitoring for at least two days following the ingestion of such drugs in overdose, is strongly recommended.

The severity of the clinical signs and symptoms of MAOI overdose varies and may be related to the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved.

Signs and symptoms of MAOI overdose may include: 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 AZILECT overdose. The following suggestions are offered based upon the assumption that AZILECT overdose may be modeled after nonselective MAO inhibitor poisoning. Treatment of overdose with nonselective 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, dietary tyramine restriction should be observed for several weeks to reduce the risk of hypertensive tyramine reaction.

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

A postmarketing report described a single patient who developed a nonfatal serotonin syndrome after ingesting 100 mg of AZILECT in a suicide attempt. Another patient who was treated in error with 4 mg AZILECT daily and tramadol also developed a serotonin syndrome. One patient who was treated in error with 3 mg AZILECT daily experienced alternating episodes of vascular fluctuations consisting of hypertension and orthostatic hypotension.

Tyramine Challenge Test

Results of a tyramine challenge study indicate that rasagiline at recommended doses is relatively selective for inhibiting MAO-B and can be used without dietary tyramine restriction. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts of tyramine (i.e., 150 mg or greater) and could potentially cause severe hypertension caused by tyramine interaction in patients taking AZILECT due to mild increased sensitivity to tyramine at recommended doses. Relative selectivity of AZILECT for inhibiting MAO-B diminished in a dose-related manner as the dose progressively increased above the highest recommended daily dose (1 mg).

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 postdose. 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 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). In vitro 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 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 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.