Summary of the safety profile: In clinical studies in Parkinson's disease patients the most commonly reported adverse reactions were: headache, depression, vertigo, and flu (influenza and rhinitis) in monotherapy; dyskinesia, orthostatic hypotension, fall, abdominal pain, nausea and vomiting, and dry mouth in adjunct to levodopa therapy; musculoskeletal pain, as back and neck pain, and arthralgia in both regimens. These adverse reactions were not associated with an elevated rate of drug discontinuation.
Tabulated list of adverse reactions: Adverse reactions are listed as follows in Tables 1 and 2 by system organ class and frequency using the following conventions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Monotherapy: The tabulated list as follows includes adverse reactions which were reported with a higher incidence in placebo-controlled studies, in patients receiving 1 mg/day rasagiline. (See Table 1.)
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Adjunct Therapy: The tabulated list as follows includes adverse reactions which were reported with a higher incidence in placebo-controlled studies in patients receiving 1 mg/day rasagiline. (See Table 2.)
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Description of selected reactions: Orthostatic hypotension: In blinded placebo-controlled studies, severe orthostatic hypotension was reported in one subject (0.3%) in the rasagiline arm (adjunct studies), none in the placebo arm. Clinical trial data further suggest that orthostatic hypotension occurs most frequently in the first two months of rasagiline treatment and tends to decrease over time.
Hypertension: Rasagiline selectively inhibits MAO-B and is not associated with increased tyramine sensitivity at the indicated dose (1 mg/day). In blinded placebo-controlled studies (monotherapy and adjunct) severe hypertension was not reported in any subjects in the rasagiline arm. In the post-marketing period, cases of elevated blood pressure, including rare serious cases of hypertensive crisis associated with ingestion of unknown amounts of tyramine-rich foods, have been reported in patients taking rasagiline. In post-marketing period, there was one case of elevated blood pressure in a patient using the ophthalmic vasoconstrictor tetrahydrozoline hydrochloride while taking rasagiline.
Impulse control disorders: One case of hypersexuality was reported in monotherapy placebo-controlled study. The following were reported during post-marketing exposure with unknown frequency: compulsions, compulsive shopping, dermatillomania, dopamine dysregulation syndrome, impulse-control disorder, impulsive behaviour, kleptomania, theft, obsessive thoughts, obsessive-compulsive disorder, stereotypy, gambling, pathological gambling, libido increased, hypersexuality, psychosexual disorder, sexually inappropriate behaviour. Half of the reported ICD cases were assessed as serious. Only single cases of reported cases had not recovered at the time they were reported.
Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes: Excessive daily sleepiness (hypersomnia, lethargy, sedation, sleep attacks, somnolence, and sudden onset of sleep) can occur in patients treated with dopamine agonists and/or other dopaminergic treatments. A similar pattern of excessive daily sleepiness has been reported post-marketing with rasagiline.
Cases of patients, treated with rasagiline and other dopaminergic medications, falling asleep while engaged in activities of daily living have been reported. Although many of these patients reported somnolence while on rasagiline 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.
Hallucinations: Parkinson's disease is associated with symptoms of hallucinations and confusion. In post-marketing experience these symptoms have also been observed in Parkinson's disease patients treated with rasagiline.
Serotonin syndrome: Rasagiline clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with rasagiline, but the following antidepressants and doses were allowed in the rasagiline trials: amitriptyline ≤ 50 mg/daily, trazodone ≤ 100 mg/daily, citalopram ≤ 20 mg/daily, sertraline ≤ 100 mg/daily, and paroxetine ≤ 30 mg/daily.
In the post-marketing period, cases of potentially life-threating serotonin syndrome associated with agitation, confusion, rigidity, pyrexia and myoclonus have been reported by patients treated with antidepressants, meperidine, tramadol, methadone, or propoxyphene concomitantly with rasagiline.
Malignant melanoma: Incidence of skin melanoma in placebo-controlled clinical studies was 2/380 (0.5%) in rasagiline 1 mg as adjacent to levodopa therapy group vs. 1/388 (0.3%) incidence in placebo group. Additional cases of malignant melanoma were reported during post-marketing period. These cases were considered serious in all reports.