AZILECT- rasagiline mesylate tablet
Teva Neuroscience, Inc.
AZILECT (rasagiline tablets) is indicated for the treatment of Parkinson’s disease (PD).
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 concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of AZILECT 0.5 mg once daily [see Warnings and Precautions (5.4), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].
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 (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
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.
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 (5.2)]. 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.
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 (6.1)].
When used as an adjunct to levodopa (Studies 3 and 4), the risk for developing post-treatment high blood pressure (e.g., systolic > 180 or diastolic >100 mm Hg) combined with a significant increase from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for 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 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 (7.1, 7.2, 7.3)].
In the postmarketing period, potentially life-threatening serotonin syndrome has been reported in patients treated with antidepressants concomitantly with 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 (7.5)].
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.
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 (2.2), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].
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 (2.3) and Clinical Pharmacology (12.3)].
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.
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