Myocardial ischemia/infarction or Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors (5.1) Arrhythmias:Discontinue FROVA if occurs (5.2) Chest/throat/neck/jaw pain, tightness, pressure, or heaviness:Generally not associated with myocardial ischemia; evaluate high risk patients for coronary artery disease (5.3) Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue FROVA if occurs (5.4) Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue FROVA if occurs (5.5) Medication overuse headache:Detoxification may be necessary (5.6) Serotonin syndrome:Discontinue FROVA if occurs (5.7, 7.3) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina FROVA is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of FROVA. Some of these reactions occurred in patients without known CAD. FROVA may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving FROVA. Do not administer FROVA if there is evidence of CAD or coronary artery vasospasm [see Contraindications (4)]. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrating the first FROVA dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following FROVA administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of FROVA. 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 FROVA if these disturbances occur. FROVA is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Contraindications (4)]. 5.3 Chest, Throat, Neck, and Jaw Pain/Tightness/Pressure Sensations of pain, tightness, pressure, and heaviness have been reported in the chest, throat, neck, and jaw after treatment with FROVA and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of FROVA is contraindicated in patients with CAD and those with Prinzmetal’s angina [see Contraindications (4)]. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, stroke and other cerebrovascular events have been reported 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 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical of migraine, other potentially serious neurological conditions need to be excluded. FROVA is contraindicated in patients with a history of stroke or TIA [see Contraindications (4)]. 5.5 Other Vasospasm Reactions FROVA, 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 a vasospastic reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before using FROVA [see Contraindications (4)]. 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 Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these 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 FROVA, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors [see Drug Interactions (7.3)]. 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 usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue FROVA if serotonin syndrome is suspected. 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 treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with FROVA. FROVA is contraindicated in patients with uncontrolled hypertension [see Contraindications (4)]. 5.9 Anaphylactic/Anaphylactoid Reactions There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving FROVA. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. FROVA is contraindicated in patients with a history of hypersensitivity reaction to FROVA [see Contraindications (4)].