Adverse reactions : תופעות לוואי

8       ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the labeling: 
•   Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina [see Warnings and Precautions (7.1)].
•   Arrhythmias [see Warnings and Precautions (7.2)].
•   Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure [see Warnings and Precautions (7.3)].
•   Cerebrovascular Events [see Warnings and Precautions (7.4)].
•   Other Vasospasm Reactions [see Warnings and Precautions (7.5)].
•   Medication Overuse Headache [see Warnings and Precautions (7.6)].
•   Serotonin Syndrome [see Warnings and Precautions (7.7)].
•   Increase in Blood Pressure [see Warnings and Precautions (7.8)].

8.1  Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Incidence in Controlled Clinical Trials
Adverse reactions to RIZALT were assessed in controlled clinical trials that included over 3700 adult patients who received single or multiple doses of RIZALT Tablets. The most common adverse reactions during treatment with RIZALT (≥5% in either treatment group and greater than placebo) were asthenia/fatigue, somnolence, pain/pressure sensation and dizziness. These adverse reactions appeared to be dose related.
Table 1 lists the adverse reactions (incidence ≥2% and greater than placebo) after a single dose of RIZALT.



Table 1: Incidence (≥2% and Greater than Placebo) of Adverse Reactions After a Single Dose of RIZALT Tablets or Placebo
% of Patients
RIZALT        RIZALT
Adverse Reactions                                 5 mg         10 mg       Placebo (N=977)      (N=1167)     (N=627)
Atypical Sensations                                 4             5            4 Paresthesia                                     3             4           <2 Pain and other Pressure Sensations                   6            9             3 Chest Pain: tightness/pressure and/or heaviness         <2            3             1 Neck/throat/jaw: pain/tightness/pressure                     <2            2             1 Regional Pain: tightness/pressure and/or heaviness        <1            2            0 Pain, location unspecified                       3            3           <2 
Digestive                                            9           13             8 Dry Mouth                                        3            3             1 Nausea                                           4            6             4 
Neurological                                        14           20           11 Dizziness                                         4            9            5 Headache                                         <2            2           <1 Somnolence                                        4            8            4 Other
Asthenia/fatigue                                  4            7             2 
The frequencies of adverse reactions in clinical trials did not increase when up to three doses were taken within 24 hours. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (including propranolol), oral contraceptives, or analgesics. The incidences of adverse reactions were not affected by age or gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions.
Other Events Observed in Association with the Administration of RIZALT In the following section, the frequencies of less commonly reported adverse events are presented that were not reported in other sections of the labeling. Because the reports include events observed in open studies, the role of RIZALT in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used RIZALT and reported an event divided by the total number of patients exposed to RIZALT (N=3716). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those defined as those occurring in at least (>)1/100 patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients.

General: Infrequent was facial edema. Rare were syncope and edema/swelling.
Atypical Sensations: Frequent were warm sensations.
Cardiovascular: Frequent was palpitation. Infrequent were tachycardia, cold extremities, and bradycardia.
Digestive: Frequent were diarrhea and vomiting. Infrequent were dyspepsia, tongue edema, abdominal distention, and thirst.
Musculoskeletal: Infrequent were muscle weakness, stiffness, myalgia and muscle cramp/spasm.
Neurological/Psychiatric: Frequent were hypoesthesia, mental acuity decreased, euphoria and tremor.
Infrequent were vertigo, insomnia, confusion/disorientation, ataxia, gait abnormality, memory impairment, and agitation.
Respiratory: Frequent was dyspnea. Infrequent was pharyngeal edema.
Special Senses: Infrequent were blurred vision and tinnitus. Rare was eye swelling.
Skin and Skin Appendage: Frequent was flushing. Infrequent were sweating, pruritus, rash, and urticaria.
Rare was erythema, hot flashes.
The adverse reaction profile seen with RIZALT RPD Wafers was similar to that seen with RIZALT Tablets.

8.2   Postmarketing Experience
The following section enumerates potentially important adverse events that have occurred in clinical practice and which have been reported spontaneously to various surveillance systems. The events enumerated include all except those already listed in other sections of the labeling or those too general to be informative. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of RIZALT in their causation cannot be reliably determined.

Neurological/Psychiatric: Seizure, serotonin syndrome
General: Allergic conditions including anaphylaxis/anaphylactoid reaction, angioedema, wheezing, and toxic epidermal necrolysis [see Contraindications (6)].
Special Senses: Dysgeusia.
Musculoskeletal: facial pain, myalgia;
Cardiovascular disorders: arrhythmia; bradycardia;
Gastrointestinal disorders: ischemic colitis;
Investigations: ECG abnormalities.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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