Special Warning : אזהרת שימוש

5     WARNINGS AND PRECAUTIONS
5.1     Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina RIZALT should not be given to patients with ischemic or vasospastic coronary artery disease. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of RIZALT. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT1 agonists, including RIZALT may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD.
Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving RIZALT. If there is evidence of CAD or coronary artery vasospasm, RIZALT should not be administered [see Contraindications (4)]. For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first RIZALT dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following RIZALT administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of RIZALT who have cardiovascular risk factors.
5.2 Arrhythmias
Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue RIZALT if these disturbances occur.
5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure
As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with RIZALT and are usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT1 agonists.
5.4 Cerebrovascular Events
Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue RIZALT if a cerebrovascular event occurs.
As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. RIZALT should not be administered to patients with a history of stroke or transient ischemic attack [see Contraindications (4)].
5.5    Other Vasospasm Reactions
5-HT1 agonists, including RIZALT, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional RIZALT doses.
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.
5.6 Medication Overuse Headache (MOH)
Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache).
Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
5.7 Serotonin Syndrome
Serotonin syndrome may occur with triptans, including RIZALT particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.5)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication. RIZALT treatment should be discontinued if serotonin syndrome is suspected [see Drug Interactions (7.4) and Patient Counseling Information (17)].
5.8 Increase in Blood Pressure
Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension receiving 5-HT1 agonists, including RIZALT. In healthy young adult male and female patients who received maximal doses of RIZALT (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed. RIZALT is contraindicated in patients with uncontrolled hypertension [see Contraindications (4)].

6     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 (5.1)].
•   Arrhythmias [see Warnings and Precautions (5.2)].
•   Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure [see Warnings and Precautions (5.3)].
•   Cerebrovascular Events [see Warnings and Precautions (5.4)].
•   Other Vasospasm Reactions [see Warnings and Precautions (5.5)].
•   Medication Overuse Headache (MOH) [see Warnings and Precautions (5.6)].
•   Serotonin Syndrome [see Warnings and Precautions (5.7)].
•   Increase in Blood Pressure [see Warnings and Precautions (5.8)].

6.1  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
RIZALT5 mg       RIZALT
Adverse Reactions                                (N=977)        10 mg       Placebo (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.

6.2   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 (4)].
Special Senses: Dysgeusia.
Musculoskeletal: facial pain, myalgia;
Cardiovascular disorders: arrhythmia; bradycardia;
Gastrointestinal disorders: ischemic colitis;
Investigations: ECG abnormalities.

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