Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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 below 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 below includes adverse reactions which were reported with a higher incidence in placebo-controlled studies, in patients receiving 1 mg/day rasagiline.

System Organ      Very common              Common                Uncommon              Not known Class
Infections and                             Influenza infestations
Neoplasms benign,                          Skin carcinoma malignant and unspecified
(including cysts and polyps)
Blood and                                  Leucopenia lymphatic system disorders
Immune system                              Allergy disorders
Metabolism and                                                   Decreased appetite nutrition disorders
Psychiatric                                Depression,                                 Impulse control disorders                                  Hallucinations*                             disorders* Nervous system    Headache                                       Cerebrovascular       Serotonin disorders                                                        accident              syndrome*, Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes*
System Organ      Very common              Common               Uncommon             Not known Class
Eye disorders                              Conjunctivitis
Ear and labyrinth                          Vertigo disorders
Cardiac disorders                          Angina pectoris      Myocardial infarction
Vascular                                                                             Hypertension* disorders
Respiratory,                               Rhinitis thoracic and mediastinal disorders
Gastrointestinal                           Flatulence disorders
Skin and                                   Dermatitis           Vesiculobullous subcutaneous                                                    rash tissue disorders
Musculoskeletal                            Musculoskeletal and connective                             pain,
tissue disorders                           Neck pain,
Arthritis
Renal and urinary                          Urinary urgency disorders
General disorders                          Fever,
and                                        Malaise administration site conditions
*See section description of selected adverse reactions

Adjunct Therapy
The tabulated list below includes adverse reactions which were reported with a higher incidence in placebo-controlled studies in patients receiving 1 mg/day rasagiline.

System Organ      Very common              Common               Uncommon             Not known Class
Neoplasms benign,                                               Skin melanoma* malignant and unspecified
Metabolism and                             Decreased appetite nutrition disorders
Psychiatric                                Hallucinations*,     Confusion            Impulse control disorders                                  Abnormal dreams                           disorders* Nervous system    Dyskinesia               Dystonia,            Cerebrovascular      Serotonin disorders                                  Carpal tunnel        accident             syndrome*, syndrome,                                 Excessive daytime
Balance disorder                          sleepiness (EDS) and sudden sleep onset (SOS) episodes*
Cardiac disorders                                               Angina pectoris Vascular                                   Orthostatic                               Hypertension* disorders                                  hypotension*


System Organ            Very common         Common               Uncommon              Not known Class
Gastrointestinal                            Abdominal pain,
disorders                                   Constipation,
Nausea and vomiting,
Dry mouth
Skin and                                    Rash subcutaneous tissue disorders
Musculoskeletal                            Arthralgia,
and connective                             Neck pain tissue disorders*
Investigations                             Decreased weight
Injury, poisoning                          Fall and procedural complications
*See section description of selected adverse reactions

Description of selected adverse 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, 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 medicinal products, 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 medicinal products, 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 (see section 4.5).

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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il