Rasagiline Mesylate: Package Insert and Label Information

RASAGILINE MESYLATE — rasagiline mesylate tablet
Mylan Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

Rasagiline tablets are indicated for the treatment of Parkinson’s disease (PD).

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Recommendations

When rasagiline tablets are prescribed as monotherapy or as adjunct therapy in patients not taking levodopa, patients may start rasagiline tablets 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 rasagiline tablets 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 rasagiline tablets are used in combination with levodopa, a reduction of the levodopa dose may be considered, based upon individual response.

The recommended doses of rasagiline tablets should not be exceeded because of risk of hypertension [see Warnings and Precautions (5.1)].

2.2 Patients Taking Ciprofloxacin or Other CYP1A2 Inhibitors

Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of rasagiline tablets 0.5 mg once daily [see Warnings and Precautions (5.4), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].

2.3 Patients with Hepatic Impairment

Patients with mild hepatic impairment should not exceed a dose of rasagiline tablets 0.5 mg once daily. Rasagiline tablets 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)].

3 DOSAGE FORMS AND STRENGTHS

Rasagiline Tablets are available containing 0.5 mg or 1 mg of rasagiline equivalent to 0.78 mg or 1.56 mg of rasagiline mesylate, respectively.

The 0.5 mg tablets are white to off-white, round tablets debossed with M on one side of the tablet and RA over 5 on the other side.
The 1 mg tablets are white to off-white, round tablets debossed with M on one side of the tablet and RA over 1 on the other side.

4 CONTRAINDICATIONS

Rasagiline tablets are 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 rasagiline tablets and initiation of treatment with these medications.

Rasagiline tablets are contraindicated for use with St. John’s wort and with cyclobenzaprine.

Rasagiline tablets are contraindicated for use with dextromethorphan because of risk of episode of psychosis or bizarre behavior.

5 WARNINGS AND PRECAUTIONS

5.1 Hypertension

Exacerbation of hypertension may occur during treatment with rasagiline tablets. 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 rasagiline tablets.

In Study 3, rasagiline tablets (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 rasagiline tablets (2%) compared to placebo (1%).

Dietary tyramine restriction is not required during treatment with recommended doses of rasagiline tablets. 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 rasagiline tablets, 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 rasagiline tablets because of the potential for large increases in blood pressure including clinical syndromes referred to as hypertensive urgency, crisis, or emergency. Rasagiline tablets are 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.

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 tablets. Serotonin syndrome has also been reported with concomitant use of rasagiline tablets with meperidine, tramadol, methadone, or propoxyphene. Rasagiline tablets are 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 rasagiline tablets. Concomitant use of rasagiline tablets 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.

Rasagiline tablets clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with rasagiline tablets, and the potential drug interaction between rasagiline tablets and antidepressants has not been studied systematically. Although a small number of rasagiline tablets-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 rasagiline tablets 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 rasagiline tablets [see Drug Interactions (7.5)].

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 rasagiline tablets 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 rasagiline tablets 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 rasagiline tablets and was more frequent in patients with Parkinson’s disease receiving rasagiline tablets than in respective patients receiving placebo (6% rasagiline tablets compared to 4% Placebo) [see Adverse Reactions (6.1)].

Before initiating treatment with rasagiline tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with rasagiline tablets 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), rasagiline tablets should ordinarily be discontinued. If a decision is made to continue these patients on rasagiline tablets, 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.

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 rasagiline tablets 0.5 mg once daily [see Dosage and Administration (2.2), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].

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 rasagiline tablets 0.5 mg once daily. Rasagiline tablets should not be used in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

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 rasagiline tablets (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 rasagiline tablets vs 33% for placebo for mild to moderate systolic blood pressure decrements (≥ 20 mm Hg), 40% for rasagiline tablets vs 33% for placebo for mild to moderate diastolic blood pressure decrements (≥ 10 mm Hg), 7% for rasagiline tablets vs 3% for placebo for severe systolic blood pressure decrements (≥ 40 mm Hg), and 9% for rasagiline tablets 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 rasagiline tablets were given as an adjunct therapy in patients not taking concomitant levodopa, there were 5 reports of orthostatic hypotension in patients taking rasagiline tablets 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 rasagiline tablets treatment and tends to decrease over time.

Some patients treated with rasagiline tablets 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 rasagiline tablets 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 rasagiline tablets 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 rasagiline tablets 0.5 mg, 9% of patients treated with rasagiline tablets 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 rasagiline tablets 1 mg/day, no patients treated with rasagiline tablets 0.5 mg/day and no placebo-treated patients.

5.7 Dyskinesia

When used as an adjunct to levodopa, rasagiline tablets 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 rasagiline tablets 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 (6.1)].

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 rasagiline tablets 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 rasagiline tablets 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 rasagiline tablets 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 rasagiline tablets 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 rasagiline tablets 0.5 mg/day, 4% in patients treated with rasagiline tablets 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 rasagiline tablets and 1 mg rasagiline tablets/day, and 0% in placebo-treated patients [see Adverse Reactions (6.1)].

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 rasagiline tablets or after starting or increasing the dose of rasagiline tablets. 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 rasagiline tablets 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 rasagiline tablets [see Drug Interactions (7.8)].

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

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