Azilect

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

• Monotherapy: AZILECT 1 mg once daily (
  2.1 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

  [see Warnings and Precautions (

  5.1

  )].
  )
• As adjunct without levodopa: AZILECT 1 mg once daily (
  2.1 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

  [see Warnings and Precautions (

  5.1

  )].
  )
• As adjunct to levodopa: AZILECT 0.5 mg once daily. Increase dose to 1 mg daily as needed for sufficient clinical response (
  2.1 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

  [see Warnings and Precautions (

  5.1

  )].
  )
• Patients taking ciprofloxacin or other CYP1A2 inhibitors: AZILECT 0.5 mg once daily (
  2.2 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

  [see Warnings and Precautions , Drug Interactions , and Clinical Pharmacology ].
  ,
  5.4 Ciprofloxacin or Other CYP1A2 Inhibitors

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

  [see Dosage and Administration , Drug Interactions , and Clinical Pharmacology ]

  .
  )
• Patients with mild hepatic impairment: AZILECT 0.5 mg once daily. AZILECT should not be used in patients with moderate or severe hepatic impairment (
  2.3 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

  [see Warnings and Precautions , Use in Specific Populations (8.6), and Clinical Pharmacology ]

  .
  ,
  5.5 Hepatic Impairment

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

  [see Dosage and Administration and Clinical Pharmacology ]

  .
  )

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.

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.

The following adverse reactions are described in more detail in the

• Hypertension
  [see Warnings and Precautions (

  5.1 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

  [see Adverse Reactions ]

  .

  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
  [see Warnings and Precautions (

  5.2 Serotonin Syndrome

  Serotonin syndrome has been reported with concomitant use of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a nonselective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl) and rasagiline (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

  [see Contraindications (

  4) and Drug Interactions ].

  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

  [see Drug Interactions (

  7.5)]

  .

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

  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

  [see Drug Interactions ]

  .

  )]
• Falling Asleep During Activities of Daily Living and Somnolence
  [see Warnings and Precautions (

  5.3 Falling Asleep During Activities of Daily Living and Somnolence

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

  Cases of patients treated with 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)

  [see Adverse Reactions (

  6.1)]

  .

  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)

  [see Drug Interactions (

  7.6)]

  . If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), 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.

  )]
• Hypotension / Orthostatic Hypotension
  [see Warnings and Precautions (

  5.6 Hypotension / Orthostatic Hypotension

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

  [see Adverse Reactions (

  6.1)]

  .

  At the 1 mg dose, the frequency of orthostatic hypotension (at any time during the study) was approximately 44% for 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%)

  [see Adverse Reactions (

  6.1)]

  .

  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
  [see Warnings and Precautions (

  5.7 Dyskinesia

  When used as an adjunct to levodopa, AZILECT may cause dyskinesia or potentiate dopaminergic side effects and exacerbate preexisting dyskinesia. In Study 3, the incidence of dyskinesia was 18% for patients treated with 0.5 mg or 1 mg 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

  [see Adverse Reactions ]

  .

  )]
• Hallucinations / Psychotic-Like Behavior
  [see Warnings and Precautions (

  5.8 Hallucinations / Psychotic-Like Behavior

  In the monotherapy study (Study 1), the incidence of hallucinations reported as an adverse event was 1.3% in patients treated with 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

  [see Adverse Reactions ].

  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 healthcare 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

  [see Drug Interactions ]

  .

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

  )]
• Impulse Control /Compulsive Behaviors
  [see Warnings and Precautions (

  5.9 Impulse Control / Compulsive Behaviors

  Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including 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
  [see Warnings and Precautions (

  5.10 Withdrawal-Emergent Hyperpyrexia and Confusion

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

  )]
  
  
  

• Meperidine: Risk of serotonin syndrome (
  4 CONTRAINDICATIONS

  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

  [see Warnings and Precautions ]

  . 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.

  Concomitant use of meperidine, tramadol, methadone, propoxyphene dextromethorphan, St. John’s wort, cyclobenzaprine, or another (selective or non-selective) MAO inhibitor

  ,
  7.1 Meperidine

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

  [see Contraindications ]

  .
  )
• Dextromethorphan: Risk of psychosis or bizarre behavior (
  4 CONTRAINDICATIONS

  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

  [see Warnings and Precautions ]

  . 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.

  Concomitant use of meperidine, tramadol, methadone, propoxyphene dextromethorphan, St. John’s wort, cyclobenzaprine, or another (selective or non-selective) MAO inhibitor

  ,
  7.2 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

  [see Contraindications ]

  .
  )
• MAO inhibitors: Risk of non-selective MAO inhibition and hypertensive crisis (
  4 CONTRAINDICATIONS

  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

  [see Warnings and Precautions ]

  . 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.

  Concomitant use of meperidine, tramadol, methadone, propoxyphene dextromethorphan, St. John’s wort, cyclobenzaprine, or another (selective or non-selective) MAO inhibitor

  ,
  7.3 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

  [see Contraindications ]

  .
  )