RASAGILINE: 2,731 Adverse Event Reports & Safety Profile

Rasagiline tablets contain rasagiline (as the mesylate), a propargylamine-based drug indicated for the treatment of idiopathic Parkinson’s disease. Rasagiline mesylate is designated chemically as: 1H-Inden-1-amine, 2, 3-dihydro-N-2-propynyl-, (1R)-, methanesulfonate. The empirical formula of rasagiline mesylate is C 12 H 13 N•CH 4 SO 3 and its molecular weight is 267.34 g/mol. Its structural formula is: Rasagiline mesylate is a white to off-white powder, freely soluble in water, ethanol 95%, and sparingly soluble in isopropanol. Each rasagiline tablet for oral administration contains 0.5 mg or 1 mg of rasagiline (equivalent to 0.78 mg or 1.56 mg of rasagiline mesylate). Each rasagiline tablet also contains the following inactive ingredients: citric acid anhydrous powder, colloidal silicon dioxide, corn starch, mannitol, partially pregelatinized maize starch, stearic acid, and talc. rasagiline-structure.jpg

1.

Indications And Usage

Rasagiline tablets are indicated for the treatment of Parkinson's disease (PD). Rasagiline tablets are monoamine oxidase (MAO)-B inhibitor (MAOI), is indicated for the treatment of Parkinson's disease ( 1 )

AND ADMINISTRATION

• Monotherapy: Rasagiline tablets 1 mg once daily ( 2.1 )
• As adjunct without levodopa: Rasagiline tablets 1 mg once daily ( 2.1 )
• As adjunct to levodopa: Rasagiline tablets 0.5 mg once daily. Increase dose to 1 mg daily as needed for sufficient clinical response ( 2.1 )
• Patients taking ciprofloxacin or other CYP1A2 inhibitors: Rasagiline tablets 0.5 mg once daily ( 2.2, 5.4 )
• Patients with mild hepatic impairment: Rasagiline tablets 0.5 mg once daily. Rasagiline tablets should not be used in patients with moderate or severe hepatic impairment ( 2.3 , 5.5 )

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.6 ), and Clinical Pharmacology ( 12.3 )]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )]</span>.

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. Concomitant use of meperidine, tramadol, methadone, propoxyphene dextromethorphan, St. John's wort, cyclobenzaprine, or another (selective or non-selective) MAO inhibitor ( 4 )

REACTIONS The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:

• Hypertension [see Warnings and Precautions ( 5.1 )]
• Serotonin Syndrome [see Warnings and Precautions ( 5.2 )]
• Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions ( 5.3 )]
• Hypotension / Orthostatic Hypotension [see Warnings and Precautions ( 5.6 )]
• Dyskinesia [see Warnings and Precautions ( 5.7 )]
• Hallucinations / Psychotic-Like Behavior [see Warnings and Precautions ( 5.8 )]
• Impulse Control /Compulsive Behaviors [see Warnings and Precautions ( 5.9 )]
• Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions ( 5.10 )] Most common adverse reactions (incidence 3% or greater than placebo):
• Rasagiline tablets monotherapy: flu syndrome, arthralgia, depression, dyspepsia ( 6.1 )
• Rasagiline tablets used as adjunct without levodopa: peripheral edema, fall, arthralgia, cough, and insomnia ( 6.1 )
• Rasagiline tablets used as adjunct to levodopa: dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, fall, and tenosynovitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc., at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 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 rasagiline tablets, Parkinson’s disease patients received rasagiline tablets 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 rasagiline tablets treatment, but also in the severity and duration of their disease, the adverse reactions are presented separately for each study.

Monotherapy

Use of Rasagiline Tablets In Study 1, approximately 5% of the 149 patients treated with rasagiline tablets 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 rasagiline tablets -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 rasagiline tablets as monotherapy and were numerically more frequent than in the placebo group in Study 1.

Table

1: Adverse Reactions* in Study 1 Rasagiline Tablets 1 mg (N=149) Placebo (N=151) % of Patients % of Patients Headache 14 12 Arthralgia 7 4 Dyspepsia 7 4 Depression 5 2 Fall 5 3 Flu syndrome 5 1 Conjunctivitis 3 1 Fever 3 1 Gastroenteritis 3 1 Rhinitis 3 1 Arthritis 2 1 Ecchymosis 2 0 Malaise 2 0 Neck Pain 2 0 Paresthesia 2 1 Vertigo 2 1 *Incidence 2% or greater in rasagiline tablets 1 mg group and numerically more frequent than in placebo group There were no significant differences in the safety profile based on age or gender.

Adjunct

Use of Rasagiline Tablets Rasagiline tablets were 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 rasagiline tablets 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 rasagiline tablets -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 rasagiline tablets as adjunct therapy without levodopa and numerically more frequent than in the placebo group in Study 2.

Table

2: Adverse Reactions* in Study 2 Rasagiline Tablets 1 mg (N=162) Placebo (N=164) % of Patients % of Patients Dizziness 7 6 Peripheral edema 7 4 Headache 6 4 Nausea 6 4 Fall 6 1 Arthralgia 5 2 Back pain 4 3 Cough 4 1 Insomnia 4 1 Upper respiratory tract infection 4 2 Orthostatic hypotension 3 1 *Incidence 2% or greater in rasagiline tablets 1 mg group and numerically more frequent than in placebo group 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 rasagiline tablets 0.5 mg/day and 7% of the 149 patients treated with rasagiline tablets 1 mg/day discontinued treatment due to adverse reactions, compared to 6% of the 159 patients who received placebo. The adverse reactions that led to discontinuation of more than one rasagiline -treated patient were diarrhea, weight loss, hallucination, and rash. The most commonly observed adverse reactions in Study 3 (incidence in rasagiline tablets -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 rasagiline tablets 1 mg/day and that were numerically more frequent than the placebo group in Study 3.

Table

3: Adverse Reactions* in Study 3 Rasagiline Tablets 1 mg (N=149)

Rasagiline Tablets

0.5 mg (N=164) Placebo (N=159) % of Patients % of Patients % of Patients Dyskinesia 18 18 10 Accidental injury 12 8 5 Nausea 12 10 8 Headache 11 8 10 Fall 11 12 8 Weight loss 9 2 3 Constipation 9 4 5 Postural hypotension 9 6 3 Arthralgia 8 6 4 Vomiting 7 4 1 Dry mouth 6 2 3 Rash 6 3 3 Somnolence 6 4 4 Abdominal pain 5 2 1 Anorexia 5 2 1 Diarrhea 5 7 4 Ecchymosis 5 2 3 Dyspepsia 5 4 4 Paresthesia 5 2 3 Abnormal dreams 4 1 1 Hallucinations 4 5 3 Ataxia 3 6 1 Dyspnea 3 5 2 Infection 3 2 2 Neck pain 3 1 1 Sweating 3 2 1 Tenosynovitis 3 1 0 Dystonia 3 2 1 Gingivitis 2 1 1 Hemorrhage 2 1 1 Hernia 2 1 1 Myasthenia 2 2 1 *Incidence 2% or greater in rasagiline tablets 1 mg group and numerically more frequent than in placebo group Several of the more common adverse reactions seemed dose-related, including weight loss, postural hypotension, and dry mouth. There were no significant differences in the safety profile based on age or gender. During all Parkinson’s disease phase 2/3 clinical trials, the long-term safety profile was similar to that observed with shorter duration exposure.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of rasagiline tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Melanoma

AND PRECAUTIONS

• May cause hypertension (including severe hypertensive syndromes) at recommended doses ( 5.1 )
• May cause serotonin syndrome when used with antidepressants ( 5.2 )
• May cause falling asleep during activities of daily living, daytime drowsiness, and somnolence ( 5.3 )
• May cause hypotension, especially orthostatic ( 5.6 )
• May cause or exacerbate dyskinesia. Decreasing the levodopa dose may lessen or eliminate this side effect ( 5.7 )
• May cause hallucinations and psychotic-like behavior ( 5.8 )
• May cause impulse control/compulsive behaviors ( 5.9 )
• May cause withdrawal-emergent hyperpyrexia and confusion ( 5.10 )

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 <span class="opacity-50 text-xs">[see Contraindications ( 4 ) and Drug Interactions ( 7.1 , 7.2 , 7.3 )]</span>. 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.5 )]</span>. 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.5 )]</span>.

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Drug Interactions ( 7.6 ), and Clinical Pharmacology ( 12.3 )]</span>.

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )]</span>.

5.6 Hypotension / Orthostatic Hypotension In Study 3, the incidence of orthostatic hypotension consisting of a systolic blood pressure decrease (&gt; 30 mm Hg) or a diastolic blood pressure decrease (&gt; 20 mm Hg) after standing was 13% with rasagiline tablets (1 mg/day) compared to 9% with placebo <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. 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 (&gt; 20 mm Hg), 40% for rasagiline tablets vs 33% for placebo for mild to moderate diastolic blood pressure decrements (&gt; 10 mm Hg), 7% for rasagiline tablets vs 3% for placebo for severe systolic blood pressure decrements (&gt; 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 pre-existing 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 rasaliline tablets and 1.8% of patients treated with placebo. Hallucination led to drug discontinuation and premature withdrawal from the clinical trial in 0.6% of patients trated with rasagiline tablets 1 mg/day and in none of the placebo-trated 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.

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 rasagiline tablets, 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 rasagiline tablets. Consider dose reduction or stopping the medication if a patient develops such urges while taking rasagiline tablets.

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.

INTERACTIONS

• Meperidine: Risk of serotonin syndrome ( 4 , 7.1 )
• Dextromethorphan: Risk of psychosis or bizarre behavior ( 4 , 7.2 )
• MAO inhibitors: Risk of non-selective MAO inhibition and hypertensive crisis ( 4 , 7.3 )

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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

7.2 Dextromethorphan The concomitant use of rasagiline tablets 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 rasagiline&apos;s MAO inhibitory activity, dextromethorphan is contraindicated for use with rasagiline tablets <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

7.3 MAO Inhibitors Rasagiline tablets are contraindicated for use with other MAO inhibitors because of the increased risk of nonselective MAO inhibition that may lead to a hypertensive crisis <span class="opacity-50 text-xs">[see Contraindications ( 4 ) ]</span>.

7.4 Sympathomimetic Medications The concomitant use of rasagiline tablets 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 rasagiline tablets and sympathomimetic medications. Severe hypertension has been reported in patients taking the recommended dose of rasagiline tablets and ophthalmic drops containing sympathomimetic medications. Because rasagiline tablets are 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 rasagiline tablets with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies.

7.5 Antidepressants Concomitant use of rasagiline tablets with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )]</span>. Concomitant use of rasagiline tablets and MAO inhibitors is contraindicated [ see Contraindications ( 4 )].

7.6 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 rasagiline tablets 0.5 mg once daily <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 ) and Clinical Pharmacology ( 12.3 )]</span>.

7.7 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 rasagiline tablets 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 rasagiline tablets 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 rasagiline tablets. Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of rasagiline tablets <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>.

7.8 Dopaminergic Antagonists It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of rasagiline tablets.